Significance Nuclear receptors (NRs) are ligand-sensing transcription factors that are crucial for the proper regulation of mammalian development, physiology, and metabolism. Their ligand-binding capability makes NRs attractive drug targets, but can also lead to the adverse side effects of prescription drugs. Our research contributes to a better understanding of how NRs are regulated in a time-of-day–dependent manner by a component of the circadian clock, cryptochrome, and is foundational to further research aiming to make drug administration routines more effective and safer.