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The MDM2 (murine double minute 2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, non-carcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other non-malignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these non-malignant diseases. In addition, a better understanding of how MDM2 works in non-malignant diseases may provide new biomarkers for their diagnosis, prognostic prediction and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several non-malignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.