MG53 (also known as tripartite motif, TRIM72) is a cardiac and skeletal muscle-specific TRIM-family protein that exhibits multiple biologic functions. MG53 participates in plasma membrane repair of the heart, skeletal muscle, and, other tissues. MG53 is essentially involved in the cardioprotection of cardiac ischemic, preconditioning, and postconditioning by activating the PI3K-Akt-GSK3β and ERK1/2 survival signaling pathways. Systemic delivery of recombinant MG53 protein ameliorates the impact of a range of injury insults on the heart, skeletal muscle, lung, kidney, skin, and brain. It is noteworthy that chronic upregulation of MG53 induces insulin resistance and metabolic diseases, such as type 2 diabetes and its cardiovascular complications, by acting as an E3 ligase to mediate the degradation of insulin receptor and insulin receptor substrate-1. MG53 negatively regulates myogenesis.