- Try to unlock all characters first. Beating the game with Isaac is certainly possible, but you may prefer other characters.
- Beating Mom for the first time is only the beginning. In fact, the game doesn't even consider it a "Mom Kill." You have to now beat Mom's Heart in subsequent playthroughs. The more times you beat Mom's Heart, the more you unlock.
- Azazel, a new character to Rebirth, is awesome in that he can fly over any obstacle to get at items you might otherwise have to pass on.
- Move around a lot when you're in a room with mobile enemies. Standing still is guaranteed to get you killed. If you feel like you're having a really great run, feel free to skip pills. Sometimes they have negative effects and can ruin your playthrough.
- Take notes and keep track of all the tarot cards. Some are good, some are bad, and some are GREAT.
- If you're not a visual learner... well, you may have some trouble with Rebirth in that case. When you use an item it's added to the item list, but only with a name and picture. Do your best to remember what each item does, and write down descriptions if that helps.
- Blow up blue flames for a chance at soul hearts.
- If you have an abundance of bombs, blow up the middle of walls in an attempt to find secret rooms.
- Deals with the devil are the ultimate risk/reward. You lose a heart, but the items offered in that room are often great.
Rebirth allows the option to input seeds, which recreates the level someone else played. It doesn't count towards progress, but it's a cool way to experience unique level layouts or use items that other people discovered. Seed codes can be found by pressing start while playing and accessing the menu, in the top left corner.
The following seeds were included by the developer and unlock various effects.
- BOOB TOOB - Arcade cabinet effect/filter
- BRWN SNKE - Leave a trail of poop when you walk
- BL1N DEYE - Invisible enemies
- KAPP A - Isaac turns gray, like the referenced Twitch emote
- DYSL EXIC - Scrambles ingame text
- PTCH BLCK - Character and tears turn black
- FART SNDS - Sound effects are now fart noises
- CAMO K1DD - Character's skin matches the color of the floor
- BASE MENT - Basement on all floors, though you can't beat the game this way
- CHAM P1ON - Every enemy is a champion (colored) version
- D0NT ST0P - Keep moving to avoid damage
- KEEP AWAY - Items mimic your character's movements
- SLOW 4ME2 - Music speeds up or slows down depending on your movement
- COME BACK - Leaving a room rewspawns enemies/bosses
- DRAW KCAB - Controls are inverted