The MDM2 and MDMX proteins, also known as HDMX and MDM4, are deregulated in many human cancers and primarily exert their oncogenic activity by inhibiting the tumor suppressor p53. Recent studies have highlighted the importance of these proteins in maintaining normal tissue homeostasis and responding to various signaling networks. This review discusses the progress made in understanding the biological functions of MDM2 and MDMX, their oncogenic roles, and the potential for developing targeted therapies. Key findings include the role of MDM proteins in blocking p53 transcriptional activity, their regulation by various signaling pathways, and the development of small-molecule and peptidic inhibitors. The review also explores the context-dependent effects of MDM proteins, their cooperation with other oncogenes, and the challenges in selecting patients for clinical trials of MDM-targeted therapies. Overall, the intricate regulatory circuit involving MDM2, MDMX, and p53 offers promising opportunities for cancer therapy, but further research is needed to fully understand the mechanisms and develop effective treatments.The MDM2 and MDMX proteins, also known as HDMX and MDM4, are deregulated in many human cancers and primarily exert their oncogenic activity by inhibiting the tumor suppressor p53. Recent studies have highlighted the importance of these proteins in maintaining normal tissue homeostasis and responding to various signaling networks. This review discusses the progress made in understanding the biological functions of MDM2 and MDMX, their oncogenic roles, and the potential for developing targeted therapies. Key findings include the role of MDM proteins in blocking p53 transcriptional activity, their regulation by various signaling pathways, and the development of small-molecule and peptidic inhibitors. The review also explores the context-dependent effects of MDM proteins, their cooperation with other oncogenes, and the challenges in selecting patients for clinical trials of MDM-targeted therapies. Overall, the intricate regulatory circuit involving MDM2, MDMX, and p53 offers promising opportunities for cancer therapy, but further research is needed to fully understand the mechanisms and develop effective treatments.