The suprachiasmatic nucleus (SCN) drives circadian rhythms of locomotor behavior by releasing factors that act on receptor sites near the third ventricle. Here we show that cardiotrophin-like cytokine (CLC) satisfies multiple criteria for a circadian regulator of locomotor activity. In the mouse, CLC is expressed in a subpopulation of SCN vasopressin neurons with a circadian rhythm that peaks during the daily period of locomotor quiescence. CLC receptors flank the third ventricle, and acute infusion of CLC into the third ventricle produced a transient blockade of locomotor activity without affecting the circadian clock. The hypothalamic infusion of neutralizing antibodies to the CLC receptor produced extra daily locomotor activity at the time when CLC is maximally expressed. These results suggest that CLC is probably an SCN output signal important for shaping daily rhythms of behavior; moreover, they indicate an unexpected role for a cytokine in adult brain function.