God, this game is so addicting. Playthroughs are short, but deceptively so, so that you end up thinking, "I'll just play one more quick game," and then you look up and notice 3 hours have past.
If this game were fremium it would have all of my money by now, as it's very good at tapping into that addictive skinner box impulse of stringing out rewards incrementally so that you keep playing that less ethically scrupulous designers make the stock and trade of fremium games.
Anyhow, just got it a couple days ago. Have unlocked all the main characters so far, save for ??? (I've yet to unlock Sheol, so...).
My most god-like/amusing run thus far was with Azazel. I got a bunch of damage upgrades along with the "remote control tears" upgrade, which turns his laser into a giant, remote controlled, circle that takes up half the screen. Stuff would instantly die as soon as I appear on screen. I only had 1 heart the entire game, but nothing could touch me.
Guppy's head (which spawns infinite glowing blue flies and has a really short recharge) turned out to be an instant win button too, which I wasn't expecting given my experience with it in the original. They swarm everyting on screen and kill fast, so you don't even have to do anything.
Over all, though, the game is a huge improvement over the original. There's a seemingly infinite variety of builds and item combinations. I don't even mind the pixel art. People earlier in the thread complained about pixels getting chunkier if a sprite is enlarged, but I actually like that. It reminds me of the old pseudo 3D games on the Genesis and SNES, which would use sprites with a set resolution and simply increase or decrease their size on the screen to simulate moving forward and backwards (Super Mario Kart and the 2D sprites in Star Fox did it alot).