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1. Put most of your health/defensive items into Jacob, he'll act as Esau's meat-shield.
2. Put all your offensive items into Esau, since he has a higher damage stat then Jacob.
3. I'd highly recommend going to Downpour and Mines for it's guaranteed double item rooms. (If you set Jacob and Esau up to where they both touch the item pedestals at the same time, you'll get both items. This also works for the Polaroid and Negative)
4. Before entering rooms, put Jacob in front of Esau so he'll be more likely to get hit then Esau.
5. Don't be afraid to take a few seconds to get J&E close together.
6. Jacob goes into cursed rooms, as red hearts are much more easy to obtain the soul hearts.
7. If you walk into a button room (room where there's a bunch of environmental hazards that can only be cleared with a button) send Jacob in and put Esau where he can't get hurt.
also devil rooms have been poopoo since afterbirth and angel rooms have been super buffed in repentance, so this is good advice for any character too
This character is cursed.