Sarcoglycans are transmembrane proteins important in the maintenance of proper muscle function. Together, the sarcoglycans form a heteromeric complex that interacts with dystrophin, dystroglycan, and filamin C to form a mechanosignaling complex. Mutations in the genes encoding sarcoglycan can produce cardiomyopathy and muscular dystrophy. Studies of patients and animal models have emphasized the variability in penetrance and severity of cardiomyopathy. In animal models of sarcoglycan mutations, muscular dystrophy develops owing to loss of the sarcoglycan complex at the membrane of skeletal myocytes. Cardiomyopathy similarly develops with evidence of focal areas of degeneration and necrosis, as well as loss of sarcoglycan at the cardiomyocyte membrane. Vascular spasm has been noted as a feature of sarcoglycan-mediated cardiomyopathy. Recent evidence suggests that disruption of the smooth muscle sarcoglycan complex is not required for the development of vascular spasm and that vascular spasm arises from a vascular smooth muscle cell-extrinsic process.