The Binding of Isaac is one of the kings of procedural generation, but Greed Mode in the upcoming DLC Afterbirth is set to give it a little more structure. Instead of a random layout, each floor has the same plan, with a store up top, some treasure rooms to the side, and large combat room as the centerpiece.
In that room, Isaac can spawn waves of enemies that drop pennies for him to spend in the store. At any point, he can take some damage to shut off a wave and cash out. Series creator Edmund McMillen explains it as a stronger risk/reward scenario with less randomness than the main game.
McMillen discusses the new mode in detail over on The Binding of Isaac website. It looks and sounds like a pretty significant change of pace from the usual basement journeys of Isaac.