The cyclin-dependent kinase inhibitor p21WAF1/CIP1 is a key mediator of p53-dependent cell cycle arrest and may play the role of a tumor suppressor in cancer. However, it has been shown that p21 may also act as an oncogene, because it inhibits apoptosis and may promote cell proliferation in some tumors. These data point out to “antagonistic duality” of p21, because it possesses anticancer and procancer properties at the same time. New data suggest that more and more proteins also may play contradictory roles in cancer thus challenging current paradigm of established oncogenes and tumor suppressors. © 2009 International Union of Biochemistry and Molecular Biology, Inc.