Cytochrome P450 (CYP) is a diverse superfamily of hemoproteins found in a large number of organisms. Most cytochrome P450 enzymes have monooxygenase activity and are involved in detoxification and hormone and lipid metabolism. In drug metabolism, the chemical modification or degradation of chemicals including exogenous and endogenous compounds, cytochrome P450 is probably the most important element of oxidative metabolism. The present understanding of the mechanisms of induction of cytochrome P450 enzymes and their regulation has made considerable progress during the last few years. However, it remains the subject of intense scientific research to better understand how the expression of cytochrome P450 enzymes is regulated at the molecular level. It has been known for three decades that the expression of cytochrome P450 gene family members is regulated by the biological clock. In addition, hepatic P450 monooxygenases metabolize melatonin, the pineal hormone whose expression is controlled by the biological clock and, in turn, resets the biological clock. This review will summarize our present understanding on how the biological clock regulates the expression and activity of cytochrome P450 enzymes to affect pharmacokinetics and detoxification and hormone and lipid metabolism and how melatonin metabolism and cytochrome P450 enzyme activity can affect circadian rhythms in mammals.