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Discussions Rules and Guidelines
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The first and most important piece of advice for A20 (and everyone is going to say this) is about mindset. Try to think less in terms of ‘builds’ or ‘must-have cards’. This way of thinking is seductive, but it can really hurt your playstyle. The cards you are offered are random and there’s a decent change that you may never see a particular card during a given run (even more so for rares). If you convince yourself that you ‘need’ a particular card to succeed, you will indirectly be setting yourself up for failure. This forum is littered with threads to the effect of “I never got x card, so I had no chance to win! This game is pure RNG and I hate it!”. But the first step to becoming a good A20 player is to realize that no particular card is necessary to win.
Instead, you should approach each card pick more intuitively. Look at the offers and consider what you need at this particular moment. Consider the elites you may face in this act. Take a peek at the boss. Look at your deck and consider what it may lack, or whether a certain card synergizes well with what you already have. Be mindful of relic synergies as well.
Be especially careful about picking cards that only work if you have certain other cards, unless you already have those cards. An Accuracy in a deck with no Shiv generators is just a curse. Ditto for a Catalyst in a deck with no poison cards, or a Limit Break in a deck with no strength boosters. These cards all excel in their combos, but they are useless until you get that combo, and there’s no guarantee you will. Better start out with some solid poison cards and THEN pick a Catalyst to boost them.
Generally speaking, you want to start out by looking for a strong offense. All elites in Act 1 are damage races in one way or another, so you need some offensive oomph to take them down before they hurt you severely or end your run. And you want to fight them, because you need those relics. Think strong attacks. Think non-strength means of dealing damage for Lagavulin (or just sufficiently heavy damage) . Think non-skill means of blocking (or just sufficiently heavy damage) for Nob. Think AOE for Sentinels.
Once you have a solid offense, you can start balancing out your deck with defense, utility and more AoE (act 2 notably has many tricky multi-enemy encounters). Early on you should be adding cards every chance you get to dilute your very poor starting cards, but once your deck begins to come together you shouldn’t be afraid to skip cards if none of the options contribute meaningfully.
Ironclad:
Spot Weakness (repeatable strength booster, generally easy to meet the condition. Cheap to play and benefits you immediately, in contrast to Demon Form).
Shrug It Off (solid defense + draw. Nothing fancy, just a good utility/survival tool)
Corruption (a really powerful card in most use cases. Obscenely so if you can pair it with Dead Branch)
Silent:
Wraith Form (priority upgrade. Only Form card that helps you immediately. Will literally save your life when played at the right time).
Corpse Explosion (extremy strong against all encounters with multiple foes that have roughly equal hp. Worth picking even in a non-poison deck)
Defect:
Buffer (Similar use case to Wraith Form. Can save you in many situations, but obs less ideal against many small hits. Amplify + Buffer+ will trivialize many encounters).
Biased Cognition (don't be too scared by the drawback. BC gives you a huge boost up front and only starts penalizing you 4-5 turns later, which is a looong time and most fights are over by then. Especially when you are so strong because of BC)
Watcher:
Blasphemy (The most insane nova card. Cheap to play and absolutely melts many encounters, esp if you get it early. Upgrade it to save it for the perfect moment. Just make sure you calculate your damage carefully, and think twice about using Mayhem/Distilled Chaos with Blasphemy in the draw pile unless it will guarantee a win when triggered.
Windmill Strike (grows really powerful fast when upgraded, sits conveniently in your hand to wait for the perfect nova moment with Wrath/Divinity. Good choice for Bottled Flame to let it start growing ASAP)
As for "directions" for specific characters, it's just like the lower levels. You're better off just figuring out the directions that run is allowing you to go with, and working within that. But there are cards that are just very good in most builds, no matter what that build is, which the person above me outlined a little. But I'd like to make some additions to that:
There's a few big ones you missed.
Echo Form, which is just ridiculously good, although it can have some of the same problems against enemies like the Time Eater and the Heart that infinite combo decks do.
Fission, which, it has been pointed out, could be considered the best card in the game, if we were to foolishly judge and rank cards on a purely standalone basis. Pound for pound, it'd be considered by far the most powerful card there is, especially when upgraded.
Glacier, which is statistically your best bet. Back when Spirelogs was around, I happened to look up some statistics for Defect wins. It seems that, of the people who uploaded their runs to Spirelogs, Glacier showed up the most often in winning decks, across all difficulties.
However, depending on just how far your strategy leans in a given direction (in this case, whether you rely on frequently evoking your orbs and channeling new ones, or frequently holding on to orbs and letting them help you passively), Glacier and Fission can actually have a counter-synergy effect going, and can interfere with the other, or make it less effective or efficient. So again, the real key is to try to understand and get to know your deck.
This MASSIVELY understates just how ridiculously careful you have to be with Blasphemy.
Another one I really like is Adrenaline on Silent. Again, nothing flashy, just makes the turn where you draw it a good bit better. You are never not happy to see it in a draw (barring the occasional niche case involving Nob or Time Eater).
Regarding Blasphemy I’d say I’m not that nervous about it any more. In most cases you have perfect information about whether Blasphemy will win you the game or not (ie: can it do so with the cards in your hand right now?). In those rare cases where it’s a gamble (say you use an attack like Wheel Kick to draw more and cross your fingers it will be attacks), you don’t have to risk it. Unless you are going to die if you don’t win anyway, in which case you might as well. I think I’ve only accidentally killed myself once or twice with Blasphemy over hundreds of hours of play - and it was always either me being careless or doing a Hail Mary thing because I had to win or I was going to die anyway.
Honestly I just take whatever I think is going to be the most impactful cards I see in act 1 that MIGHT play nice later on with other things. I really don't start even thinking about 'builds' until I'm at least halfway into act 1 and have some relics and a chunk of cards to try to make sense of.