Even apparently simple tasks, like searching for analogs, which are rapid for millionscale chemical libraries, are ill-suited to handle multi-10-billion scale collections because the indexes are too big to fit in rapid access computer memory. The problem is just as apparent for more complex questions like molecular docking, which, though they scale linearly, are computationally intensive. Computer clusters capable of docking hundreds of millions of molecules in days or weeks now struggle with billions. New methods to work with this space are urgently needed.