Protein p21Cip1/Waf1 is a cyclin-dependent kinase inhibitor, which is important in the response of cells to genotoxic stress and a major transcriptional target of p53 protein. Based on the localization, p21Cip1/Waf1 protein executes various functions in the cell. In the nucleus p21Cip1/Waf1 binds to and inhibits the activity of cyclin dependent kinases Cdk1 and Cdk2 and blocks the transition from G1 phase into S phase or from G2 phase into mitosis after DNA damage. This enables the repair of damaged DNA. p21Cip1/Waf1 was also found as an important protein for the induction of replication senescence as well as stress-induced premature senescence. In the cytoplasm, p21Cip1/Waf1 protein has an anti-apoptotic effect. It is able to bind to and inhibit caspase 3, as well as the apoptotic kinases ASK1 and JNK. The function of p21Cip1/Waf1 in response to a DNA damage probably depends on the extent of the damage. In the case of low-level DNA damage, the expression of p21Cip1/Waf1 is increased, it induces cell cycle arrest, and performs also anti-apoptotic activities. However, after extensive DNA damage the amount of p21Cip1/Waf1 protein is decreased and the cell undergoes apoptosis. Dual function of p21Cip1/Waf1 was also observed in cancerogenesis. On the one hand, p21Cip1/Waf1 acts as a tumor suppressor; on the other hand it prevents apoptosis and acts as an oncogene. Better understanding of the role of p21Cip1/Waf1 in various conditions would help to develop better cancer-treatment strategies. J. Cell. Biochem. 112: 3502–3506, 2011. © 2011 Wiley Periodicals, Inc.