PP2B is a Ca2+/calmodulin-dependent protein phosphatase that is ubiquitously expressed in mammals. Among other actions, it is an effector mechanism in NMDA-mediated glutamate neurotransmission as well as a regulator of GSK3beta and MAPK signaling cascades. Because all of these mechanisms have demonstrable roles in the control of circadian rhythyms, we hypothesized that PP2B would be a key regulator of rhythm generation and entrainment, and that through inhibition of its phosphatase activity, the circadian system would be affected by immunosuppressant drug therapy. We report here that immunosuppressant drugs (cyclosporin A, FK506) (1) block the circadian responses to light that underlie photic entrainment; (2) produce circadian phase shifts with a characteristic nonphotic profile; and (3) disrupt circadian rhythm expression when applied chronically. These results indicate a role for PP2B in circadian rhythm generation and entrainment. In addition, because rhythm disturbance has been implicated in impairment of both physical and mental health, we suggest that the use of immunosuppressants would be safer and more efficacious if their impacts on circadian rhythmicity were taken into account.