Cell division requires the coordinated assembly of cyclins and cyclin-dependent kinases that promote cell-cycle progression through S phase and mitosis. Two families of cyclin-dependent kinase inhibitors prevent abnormal or premature proliferation by blocking cyclin kinase activity. Expression of the cyclin-dependent kinase inhibitor p21, a member of the Cip/Kip family, increases when cells are damaged. In addition to controlling cell-cycle progression, p21 participates in DNA repair and apoptotic processes. The recent appreciation that p21 regulates cell survival and death implies that it is a master regulator of cell fate. This review discusses how p21 can affect the cellular response to oxidative stress.