The article provides a comprehensive review of MDM2 inhibitors for cancer therapy, covering their discovery, development, and clinical trials. MDM2, a protein that regulates p53, has emerged as a promising target for cancer therapy due to its roles in carcinogenesis, drug resistance, and immune modulation. The review highlights the various strategies used to target MDM2, including blocking the MDM2-p53 interaction, directly targeting MDM2, and using proteolysis-targeting chimeras (PROTACs). Despite extensive preclinical and clinical studies, no FDA-approved MDM2 inhibitor is currently available. The article discusses the challenges and future directions in MDM2 inhibition, emphasizing the need for further research to optimize the therapeutic potential of MDM2 inhibitors. Key findings include the discovery of novel MDM2 inhibitors, the combination of MDM2 inhibitors with other treatments, and the exploration of dual inhibitors to target both MDM2 and MDMX. The review also addresses the role of MDM2 in cancer stem cells, chemoresistance, and immune checkpoint inhibitor resistance, highlighting the complex and multifaceted nature of MDM2's functions in cancer.The article provides a comprehensive review of MDM2 inhibitors for cancer therapy, covering their discovery, development, and clinical trials. MDM2, a protein that regulates p53, has emerged as a promising target for cancer therapy due to its roles in carcinogenesis, drug resistance, and immune modulation. The review highlights the various strategies used to target MDM2, including blocking the MDM2-p53 interaction, directly targeting MDM2, and using proteolysis-targeting chimeras (PROTACs). Despite extensive preclinical and clinical studies, no FDA-approved MDM2 inhibitor is currently available. The article discusses the challenges and future directions in MDM2 inhibition, emphasizing the need for further research to optimize the therapeutic potential of MDM2 inhibitors. Key findings include the discovery of novel MDM2 inhibitors, the combination of MDM2 inhibitors with other treatments, and the exploration of dual inhibitors to target both MDM2 and MDMX. The review also addresses the role of MDM2 in cancer stem cells, chemoresistance, and immune checkpoint inhibitor resistance, highlighting the complex and multifaceted nature of MDM2's functions in cancer.