Integration of physiologically relevant in vitro assays at the earliest stages of drug discovery may improve the likelihood of successfully translating preclinical discoveries to the clinic. Assays based on in vitro-differentiated, human pluripotent stem cell (IVD hPSC)-derived cells, which may better model human physiology, are starting to impact the drug discovery process, but their implementation has been slower than originally anticipated. In this Perspective, we discuss imperatives for incorporating IVD hPSCs into drug discovery and the associated challenges.