MDM2 and MDMX are key regulators of p53, a tumor suppressor protein, and are involved in oncogenesis. They inhibit p53 activity by promoting its degradation, which is crucial for tumor development. Recent studies have shown that MDM2 and MDMX are major negative regulators of p53 and are now considered as potential therapeutic targets. The MDM2-MDMX-p53 network is critical for maintaining tissue homeostasis and responding to oncogenic and therapeutic challenges. MDM2 and MDMX have distinct roles in regulating p53, with MDM2 primarily functioning as an E3 ubiquitin ligase, while MDMX has a longer half-life and can modulate MDM2 activity. Both proteins are involved in various signaling pathways and their dysregulation contributes to cancer progression. The regulation of MDM2 and MDMX is complex, involving transcriptional, post-transcriptional, and post-translational mechanisms. Phosphorylation and ubiquitination play critical roles in modulating their activity. miRNAs also influence MDM2 and MDMX expression, affecting p53 function. In cancer, the overexpression of MDM2 and MDMX is often associated with poor prognosis, and their inhibition has shown promise in preclinical studies. Targeting MDM2 and MDMX has been explored through various approaches, including small-molecule inhibitors, peptidic inhibitors, and protein-protein interaction (PPI) antagonists. Nutlin 3a, a MDM2 inhibitor, has shown efficacy in preclinical models and is currently in clinical trials. Other compounds, such as RG7112, a dual inhibitor of p53-MDM2 and p53-MDMX, have also shown potential. Combination therapies involving MDM2/MDMX inhibitors and other agents, such as BRAF inhibitors, have shown synergistic effects in cancer treatment. The development of effective therapies targeting MDM2 and MDMX requires a deeper understanding of their regulatory mechanisms and the context in which they function. Future research should focus on identifying biomarkers for patient selection and optimizing therapeutic strategies to improve outcomes in cancer patients.MDM2 and MDMX are key regulators of p53, a tumor suppressor protein, and are involved in oncogenesis. They inhibit p53 activity by promoting its degradation, which is crucial for tumor development. Recent studies have shown that MDM2 and MDMX are major negative regulators of p53 and are now considered as potential therapeutic targets. The MDM2-MDMX-p53 network is critical for maintaining tissue homeostasis and responding to oncogenic and therapeutic challenges. MDM2 and MDMX have distinct roles in regulating p53, with MDM2 primarily functioning as an E3 ubiquitin ligase, while MDMX has a longer half-life and can modulate MDM2 activity. Both proteins are involved in various signaling pathways and their dysregulation contributes to cancer progression. The regulation of MDM2 and MDMX is complex, involving transcriptional, post-transcriptional, and post-translational mechanisms. Phosphorylation and ubiquitination play critical roles in modulating their activity. miRNAs also influence MDM2 and MDMX expression, affecting p53 function. In cancer, the overexpression of MDM2 and MDMX is often associated with poor prognosis, and their inhibition has shown promise in preclinical studies. Targeting MDM2 and MDMX has been explored through various approaches, including small-molecule inhibitors, peptidic inhibitors, and protein-protein interaction (PPI) antagonists. Nutlin 3a, a MDM2 inhibitor, has shown efficacy in preclinical models and is currently in clinical trials. Other compounds, such as RG7112, a dual inhibitor of p53-MDM2 and p53-MDMX, have also shown potential. Combination therapies involving MDM2/MDMX inhibitors and other agents, such as BRAF inhibitors, have shown synergistic effects in cancer treatment. The development of effective therapies targeting MDM2 and MDMX requires a deeper understanding of their regulatory mechanisms and the context in which they function. Future research should focus on identifying biomarkers for patient selection and optimizing therapeutic strategies to improve outcomes in cancer patients.