MDM2 has emerged as a promising target for cancer therapy due to its role in carcinogenesis, immunity, and response to various cancer treatments. Since the first MDM2 inhibitor was reported over 30 years ago, numerous approaches have been explored to inhibit MDM2, with hundreds of small molecule inhibitors evaluated in preclinical studies and many tested in clinical trials. Despite these efforts, no FDA-approved MDM2 inhibitor is currently available. However, several promising agents are undergoing clinical trials, including those granted FDA orphan drug or fast-track status. This review summarizes the research on MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of p53 status. It also discusses how preclinical and clinical studies have moved towards combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. The review highlights current challenges and future directions for accelerating the clinical application of MDM2 inhibitors. Targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 is implicated. MDM2 plays a critical role in regulating cancer cell proliferation, apoptosis, DNA repair, and metastasis. It is also involved in resistance to various cancer therapies, including chemotherapy, radiotherapy, and immune checkpoint inhibitors. MDM2's functions extend beyond p53-dependent mechanisms, contributing to genomic instability, cancer stem cell properties, and immune modulation. The development of MDM2 inhibitors has focused on blocking the MDM2-p53 interaction, directly targeting MDM2, and using proteolysis targeting chimeras (PROTACs). Various small molecule inhibitors, including Nutlins, spiro-oxindole derivatives, and piperidinones, have been developed to target MDM2. Despite these advances, challenges remain in achieving the desired therapeutic effects without significant side effects. Ongoing research aims to overcome these challenges and improve the clinical application of MDM2 inhibitors.MDM2 has emerged as a promising target for cancer therapy due to its role in carcinogenesis, immunity, and response to various cancer treatments. Since the first MDM2 inhibitor was reported over 30 years ago, numerous approaches have been explored to inhibit MDM2, with hundreds of small molecule inhibitors evaluated in preclinical studies and many tested in clinical trials. Despite these efforts, no FDA-approved MDM2 inhibitor is currently available. However, several promising agents are undergoing clinical trials, including those granted FDA orphan drug or fast-track status. This review summarizes the research on MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of p53 status. It also discusses how preclinical and clinical studies have moved towards combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. The review highlights current challenges and future directions for accelerating the clinical application of MDM2 inhibitors. Targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 is implicated. MDM2 plays a critical role in regulating cancer cell proliferation, apoptosis, DNA repair, and metastasis. It is also involved in resistance to various cancer therapies, including chemotherapy, radiotherapy, and immune checkpoint inhibitors. MDM2's functions extend beyond p53-dependent mechanisms, contributing to genomic instability, cancer stem cell properties, and immune modulation. The development of MDM2 inhibitors has focused on blocking the MDM2-p53 interaction, directly targeting MDM2, and using proteolysis targeting chimeras (PROTACs). Various small molecule inhibitors, including Nutlins, spiro-oxindole derivatives, and piperidinones, have been developed to target MDM2. Despite these advances, challenges remain in achieving the desired therapeutic effects without significant side effects. Ongoing research aims to overcome these challenges and improve the clinical application of MDM2 inhibitors.