Sarcoglycan is a transmembrane, dystrophin-associated protein expressed in skeletal and cardiac muscle. The murine-sarcoglycan gene was disrupted using homologous recombination. Mice lacking-sarcoglycan showed pronounced dystrophic muscle changes in early life. By 20 wk of age, these mice developed cardiomyopathy and died prematurely. The loss of-sarcoglycan produced secondary reduction ofand-sarcoglycan with partial retention of-and-sarcoglycan, suggesting that-,-, and-sarcoglycan function as a unit. Importantly, mice lacking-sarcoglycan showed normal dystrophin content and localization, demonstrating that myofiber degeneration occurred independently of dystrophin alteration. Furthermore,-dystroglycan and laminin were left intact, implying that the dystrophin–dystroglycan–laminin mechanical link was unaffected by sarcoglycan deficiency. Apoptotic myonuclei were abundant in skeletal muscle lacking-sarcoglycan, suggesting that programmed cell death contributes to myofiber degeneration. Vital staining with Evans blue dye revealed that muscle lacking-sarcoglycan developed membrane disruptions like those seen in dystrophin-deficient muscle. Our data demonstrate that sarcoglycan loss was sufficient, and that dystrophin loss was not necessary to cause membrane defects and apoptosis. As a common molecular feature in a variety of muscular dystrophies, sarcoglycan loss is a likely mediator of pathology.