Cancer develops due to an imbalance between cell proliferation and cell death. Various mechanisms of carcinogenesis as well as of novel anticancer agents that could be targeted for the treatment of cancer have been proposed by different studies. Among these, p21 is recognized as a potent cyclin-dependent kinase inhibitor that facilitates cell-cycle arrest by interacting with different stimuli such as p53, DNA repair process, CDK, E2F1, MYC, PCNA, STAT3 AP4, proteasomes, K1F, CDX2, and ER-α. p21 acts both as a tumor-suppressor gene and an inhibitor of apoptosis by interacting with various molecules and transition factors. In this review, we discuss the complex role of p21 in the development of cancer and as a target in its treatment. We conclude that, in the future, the tumor-suppressor activity of p21 should be the focus of a novel treatment strategies, which may lead to the devolvement of new and selective anti-cancer agents for the targeted therapy of cancers.