The tumor suppressor protein p53 mediates critical cellular functions including regulation of cell cycle, apoptosis, DNA repair, and senescence. This protein has been found to be inactivated or functionally down-regulated in several malignancies such as Li- Fraumeni syndrom, hepatocellular carcinoma, breast cancer, cervical cancer, and acute myeloid leukemia. Thus, p53 represents an attractive target for therapeutic design and development of new anticancer agents. The most clinically used cytotoxic agents target stabilization of wt-p53 through DNA damage and are associated with several unwanted and life threatening side effects. There are a number of recently developed approaches that hold promise for non-genotoxic reactivation of p53. Earlier, we have reported various inhibitors of p53 and their importance to prevent unwanted death of normal cells in a variety of diseases . To extend p53 protein as new target for anticancer agents, in this review we discussed the mechanisms of p53 inactivation. Subsequently, we described some of recently developed non-genotoxic activators of p53 and their significance in various neoplastic disorders. Additionally, we summarized advantages of nongenotoxic p53-activating agents over conventional anticancer therapy and challenges in future of p53 based therapy.