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Abstract Drosophila Cryptochrome (CRY) is an essential photoreceptor that mediates the resetting of the circadian clock by light. in vitro studies demonstrated a critical role of redox cycling of the FAD cofactor for CRY activation by light. However, it is unknown if CRY responds to cellular redox environment to modulate the circadian clock. We report here that the mitochondrial respiratory chain impinges on CRY activity. Inhibition of complex III and V blocks CRY-mediated degradation of TIMELESS (TIM) in response to light, and also blocks light-induced CRY degradation. On the other hand, inhibition of complex I facilitates TIM degradation even in the dark. Mutations of critical residues of the CRY C-terminus promote TIM degradation in the dark, even in the presence of complex III and V inhibitors. We propose that complex III and V activities are important for activation of CRY in response to light. Interestingly, we found that transcriptional repressor functions of Drosophila and mammalian CRY proteins are not affected by mitochondrial inhibitors. Together these data suggest that the two functions of CRY have different sensitivity to disruptions of the mitochondrial respiratory chain: one is sensitive to mitochondrial activities that enable resetting, the other is insensitive so as to sustain the molecular oscillator.