Try new things
There are very few skills that are useful at all stages of the game, and every build will have to upgrade or evolve after defeating some walls. Resetting is free, or can be. While test driving a new build, try to restrict the mana investment to either a small percent of what you have or an amount you can earn back quickly. Trying a new build and paying attention to where its strengths and weaknesses come from will make all your future builds stronger.

Making a build

• Pick a damage source
  
• Pick multiplying skills
  
• Stack damage multipliers
  
• Divide souls between multipliers

Focus on mana generation or damage
Most skills multiply off each other, which means spending half your skill points on mana and half on damage reduces your damage and mana by more than just 50%.

Split souls between DPS (or mana) multiplying sources
As a general rule of thumb, splitting souls evenly between things that multiply off each other gives you the best output. This refers to captains and skeletons, not goblins and skeletons which don’t increase each other’s damage.

Goblins vs skeletons
Goblins and skeletons' damage are so close that both are viable options. Goblins ramp up a bit so they might be a bit better if you're playing less actively.

Cultists vs mages
Both work great and are much better than focus and the skills that improve focus. Cultists can be min-maxed in the early game a bit more by waiting until a good mana amp before cashing in, but mages are close in mana generated and are less complex.

Fireball
Fireball is a unique skill. Mana spent becomes direct damage. Any damage multipliers increase your damage per mana spent. More skill points in fireball improves the efficiency of damage conversion, but not by much. To get more out of fireball, you can either generate more mana or have a higher damage multiplier.

Damage multipliers

• Captains (9+): captains remain relevant as one of the best damage multipliers, as it scales with soul count, where other damage multipliers have a cap. They perform particularly well with invocations (active spells) since they don't use souls to increase damage directly.
  
• Mana amplification (9+): mana amp might be equally strong as captains when they're unlocked, but it doesn't scale as well. There are some later synergies, but they are a bit too weak to be worth investing in.
  
• Incinerate (17+): Not bad and it's very efficient at low skill investment. By the time synergies are introduced for encantations, there are better skills to use in place of incinerate.

Viable damage skills (at least at time of unlock)

• Skeleton (1)
  
• Goblin (1)
  
• Bone spear (5)
  
• Fireball (9)
  
• Poison dagger (17)
  
• Devil (21)

Augments (upgrades)
The early game can be cleared quickly without saving up to unlock augments. After camels or at least blood comms, augments take a lot less time to unlock (at least through Imbue. Entreat might still take a while).

Damage multipliers
There are no new, viable damage multipliers in this phase (sorry solitude). In the early game, damage multiplier sources are close in power, but captains continue to scale up as souls capacity increases. Other sources are still viable, however, and there’s nothing stopping a build from using all damage multipliers. Just keep in mind stacking damage multipliers is not multiplicative, but additive.

Viable damage skills

• Skeleton - with overseers and heighten
  
• Devil - 30+ will slow down without entreat
  
• Mystics
  
• Fireball
  
• Poison dagger - with Imbue
  
• Ghosts

Mana fang
In its current state, mana fang changes the whole dynamic of the game. From here on, there won't be a need to switch builds for mana generation.

Rupture and Volcano
Rupture, on its surface, is a fairly minor damage multiplier. Soon after receiving rupture sources (spider and boozooka), there will be skills that synergize with it. Volcano, in particular, can be a very strong addition to most builds, but requires active play and a source of rupture in the build. It’s also worth pointing out that boozooka is an invocation spell that sorcerers can copy.

Sacrificing
Many new skills allow sacrificing certain units, or benefit from sacrificing units. Most sacrifice sources need to be actively cast. Units that are consumed still count as sacrifices, but the rates are generally very low.

Sacrifice sources

• Manual sacrifice - dragon scale clicks 25/s
  
• Insect plague - 2 per cast, 50/s
  
• Chain lightning - 5 per cast, 125/s. More with sorcerers
  
• Blood golems - 1000/s? more on this later
  
• Huggers - 2 or 3/s. Passive
  
• Devils - 2/min per devil (100 devils = 3/s). Passive

Damage multipliers

• Gates of Hell (45)
  
• Bard(53) - The first point is worth a lot more than the next 19
  
• Volcano(57)
  
• General & Captains (57)
  
• Knights(57)

Viable Skills
It’s probably easier to name the skills that don’t work but here are some good ones

• Fireball
  
• Devil - needs Entreat
  
• Ghost
  
• Dragon
  
• Knight

Ancient Security (Kill) walls
The later kill walls will pose a problem for many builds, since they can wipe out key units quickly. Their first target is always a melee minion, which includes skeletons, insects, and huggers, all of which make great fodder. Builds that require sacrificing and replacing units (like dragons and devils) might struggle balancing unit counts, and knights will struggle even more on these walls since knights are also melee minions. Bubble shield helps, but it only solves the problem after unlocking ultimate mastery.

Mastery skills
This might be obvious, but higher level mastery skills are always worth skilling before lower ones since they give everything the lower mastery gives and more. In most cases, add the mastery skills to the build last. Going from 50 to 51 in a skill only gives a 2% increase.

Damage Multipliers

• Gates of Hell - mana echoes is really strong with this
  
• Bards and Jesters
  
• Captains and Generals - very expensive in souls to get a good multiplier
  
• Volcano - Reverse Engineering helps a lot depending on rupture rate
  
• Bone Tsunami

Viable Skills
Most skills can work again, but some good ones are:

• Skeletons - Slice of Hell and Heavy Weapons are strong skills
  
• Ghosts - falls off in in 90+, but can make it all the way
  
• Huggers/Archdevils
  
• Goblin Grenades
  
• Dragons
  
• Gobuchet

Endless won’t be fun for everyone, but it’s a sandbox to test builds and find the strongest ones. At some point, every skill will hit a wall where it takes days to clear a wall. At least there’s no heal walls

Fracture
Most walls are cleared too fast for this to be worthwhile, but in endless fracture can be a great damage multiplier. 30k+ damage mult from fracture is not too difficult to manage.

Corruption Orb
While there is no limit to the corruption orb level, there are only 3 upgrades that can be unlocked. These upgrades will continue to scale up with levels.

Any of these tips or concepts might be something that gets fixed or changed in a later update.

Poison Prestacking
This is mostly only relevant for speedruns, but poison can be stacked on a wall before the wall appears. The wall won’t take damage until it fully appears, but the first poison tick can already be near max.

Blood Golem spam
Blood golems sacrifice all cultists and goblins instantly, which makes it the fastest sacrifice option, only limited by the summon rate and lag. It doesn’t seem intentional, as the blood golem skill is disabled for a second if you click it, but holding it down works.

Volcano Autoclicker
Volcano does not work too well when holding it down, since it will use most of the 300 max volcanoes on low rupture counts. 300 volcanoes with 5 ruptures is only 3000 multiplier, whereas 300 volcanoes with 200 ruptures is 120k multiplier. I use an autoclicker set to click 2.5 times per second, or 300 times every 2 minutes.

Multiple Hold or Passive Hold
By alt-tabbing while holding a button and clicking to re-focus the window (sometimes you have to click on a button like the skills tab), any button that can be held down permanently until you click the button again to release the hold. This allows some active builds to be played passively, but more importantly it opens up sacrifice opportunities. Archdevils are the only good passive sacrifice source, but holding down blood golems or insect plague can enable many builds to benefit from hell gates, fractures and volcanoes.

Save Backups or editing
The save file can be found in your user directory:
<<your main drive>>:\Users\<<User>>\AppData\LocalLow\Adam Travers\Journey to Incrementalia
The file is Incrementalia-save-file.txt. You can save this file's contents elsewhere as often as you wish. While the game is closed, you can swap the contents of this file with a backup save to load from that state. The option to edit your save is there if you wish, but your results may vary based on what you try and edit (make a backup first!)

These are just some fun ideas the community has come up with that give a playthrough a different flavor. I have completed all of these challenges, and can confirm they can be completed. Most challenges take a day or two, the longest of them took about a week. Let me know if you have any ideas!

No Items (Easy) - Mana fang changes the game so much that the game feels different without it.
Only Skeletons (Medium | NG0 + 1 only) - Skeletons are the only damage source allowed. This is anything that appears in the top right. No insect plagues, boozookas, volcanoes, for example. Be careful leveling the corruption orb as it summons insects and huggers at higher levels. Wall 50 can be brutal
One Soul (Medium | NG0 + 1 only) - Beat the game with only one soul. This took a lot less time than I expected, only a few hours after an overnight afk for mana. Later NGs add Skeleton key, which is definitely not possible with this challenge.
Polar Opposites (Medium | NG0?) - Beat the game twice, but don't use any of the same skills in either run. This takes some planning. I have't tested NG1-F.
Triple Runs (Hard | NG0?) - Same as above, but three wins that don't share any of the same skills. This took me a week to complete and I had to create save backups to return to if one of the runs got stuck. NG+s are likely not possible because of immunity walls.
Skill Draft (Medium) - Only 1 skill from each set allowed. This carries across skill resets, meaning for the rest of the run the 2 skills not chosen are banned.
No Resets (Easy) - No resetting skills.
Bone Only (Medium | All NGs) - Only bone-themed skills as a source of damage. The top right can never show damage from a skill other than: Skeletons, Bone Bombs, Mystics. Later walls required some devious tricks to solve.

Some tricks for solving tougher wall mod challenges (spoilers in case you'd like to figure them out yourself).

• Bone Only specific - when walls are immune to a certain damage type, using utility skills of that type that deal damage don't break the rule of entering the damage sources in the top right. Most notable, insects and blood golems for sacrifices
  
• Zombified mod - Exiting the game and restarting resets the timer.
  
• Early NGs trick - equipped artifacts in the first 2 slots don't get reset when resetting prestige points. Putting wade's feather in slot 1 and resetting saves 3 or 4 prestige points.