The circadian clock in mammalian organisms is generated by a transcription-translation feedback loop (TTFL) which controls many biochemical pathways at the cellular level and physiology and behavior at the organismal level. Cryptochrome (Cry) is a key protein in the negative arm of the TTFL. It has been found that Cry mutation in cells with p53-null genotype increased their sensitivity to apoptosis by genotoxic agents. Here, I show that this increased sensitivity is due to upregulation of the p53 gene family member p73 in response to DNA damage. As a consequence, when tumors arising from oncogenic Ras-transformed p53-/- and p53-/-Cry1-/-Cry2-/- cells are treated with the anticancer drug, oxaliplatin, the p53-/- tumors continue to grow whereas the p53-/-Cry1-/-Cry2-/- tumors exhibit extensive apoptosis and stop growing. This finding provides a mechanistic foundation for overcoming the resistance of p53-deficient tumor cells to apoptosis induced by DNA-damaging agents and suggests that disruption of cryptochrome function may increase the sensitivity of tumors with p53 mutation to chemotherapy.