Cancer is an uncontrolled and abnormal growth of cells in the body. The gene that guards the cell cycle and functions as a tumor suppressor is p53 (also called the guardian of the genome) which is encoded by the TP53 gene. Various events, like DNA damage, heat shock, hypoxia, and oncogene overexpression, result in the activation of p53. Thus, it plays a major role as a regulatory protein that regulates various diverse biological responses, responsible for genetic stability by preventing genome mutation. More than 50% of mutations in human cancers, along with the increase in expression of the murine double minute 2 gene (mdm2), has been found as one of the reasons for cancer progression. Murine double minute 2 (MDM2) is the negative regulator of the p53 gene, forming an autoregulatory feedback loop controlling each other cellular levels. Murine double minute 2 is a unique E3 ubiquitin ligase protein that is responsible for ubiquitination and degradation of the p53 gene. Many drugs/compounds have been developed for reactivation of the p53 gene by inhibiting MDM2 interaction with p53, using MDM2 antagonism, and inhibiting E3 ubiquitination of p53. Many compounds have entered clinical trials in hematological malignancies. This review will throw some light on the reactivation of the p53 gene by MDM2 and its homologs.