The suprachiasmatic nucleus (SCN)-often referred to as the master circadian clock-is essential in generating physiologic rhythms and orchestrating synchrony among circadian clocks. This study tested the hypothesis that periodic motivation induced by rhythmically pairing 2 reinforcing stimuli [methamphetamine (METH) and running wheel (RW)] restores autonomous circadian activity in arrhythmic SCN-lesioned (SCNX) C3H/HeN mice. Sham-operated and SCNX mice were treated with either METH (1.2 mg/kg, i.p.) or vehicle in association, dissociation, or absence of an RW. Only the association of METH treatment and restricted RW access successfully re-established entrained circadian rhythms in mice with SCNX. RW-likely acting as a link between the circadian and reward systems-promotes circadian entrainment of activity. We conclude that a conditioned drug response is a powerful tool to entrain, drive, and restore circadian physiology. Furthermore, an RW should be recognized as a potent input signal in addition to the conventional use as an output signal.-Rawashdeh, O., Clough, S. J., Hudson, R. L., Dubocovich, M. L. Learned motivation drives circadian physiology in the absence of the master circadian clock.