Dysregulation of the production of reactive oxygen species (ROS) determines cellular function. Cytochrome P450s (CYPs) regulates ROS production and contributes to the process of cell death. This review summarizes our recent findings, focusing on the involvement of CYPs in pathophysiology induced by ROS. 1. Quinone toxicity in hepatocytes: CYPs require electrons supplied from NADPH-cytochrome P450 reductase (NPR) during the process of metabolism. NPR also provides electrons to quinone compounds, which compete with CYPs over electrons. Inhibition of CYPs shifts NPR's electron flow more to quinones, which accelerates the redox cycle to enhance ROS production and quinone toxicity. 2. Myocardial ischemia-reperfusion injury: Reperfusion of blood flow after coronary artery occlusion induces cell damage, as evident by the extension of myocardial infarct size and caspase-independent cell apoptosis. CYP2C6 appears to be a source for ROS production, since sulfaphenazole, a selective inhibitor of CYP2C6, reduces this damage. ROS produced by CYP2C6 during the reperfusion causes translational activation of Noxa and BimEL, as well as the suppression of caspase activation, resulting in caspase-independent apoptosis. 3. Primary hepatocyte apoptosis: Inhibition of catalase and glutathione peroxidase increases intracellular ROS and elicits caspase-independent hepatocyte apoptosis. SKF-525A, a pan-CYP inhibitor, suppresses these ROS increases and hepatocyte apoptosis. Increased ROS activates ERK and AP-1 by inhibition of tyrosine phosphatase, and inhibits BimEL degradation by proteasome. These results in the accumulation of mitochondrial BimEL, which then induces the release of cytochrome c and endonuclease G (EndoG). Increased ROS also keeps caspases inactivated. As a result, EndoG executes nucleosomal DNA fragmentation.