Muscular dystrophy is a progressive muscle wasting disease that is thought to be initiated by unregulated Ca2+ influx into myofibers leading to their death. Store-operated Ca2+ entry (SOCE) through sarcolemmal Ca2+ selective Orai1 channels in complex with STIM1 in the sarcoplasmic reticulum is one such potential disease mechanism for pathologic Ca2+ entry. Here, we generated a mouse model of STIM1 overexpression in skeletal muscle to determine whether this type of Ca2+ entry could induce muscular dystrophy. Myofibers from muscle-specific STIM1 transgenic mice showed a significant increase in SOCE in skeletal muscle, modeling an observed increase in the same current in dystrophic myofibers. Histological and biochemical analysis of STIM1 transgenic mice showed fulminant muscle disease characterized by myofiber necrosis, swollen mitochondria, infiltration of inflammatory cells, enhanced interstitial fibrosis and elevated serum creatine kinase levels. This dystrophic-like disease in STIM1 transgenic mice was abrogated by crossing in a transgene expressing a dominant-negative Orai1 (dnOrai1) mutant. The dnOrai1 transgene also significantly reduced the severity of muscular dystrophy in bothmdx(dystrophin mutant mice) and δ-sarcoglycan-deficient (Sgcd−/−) mouse models of disease. Hence, Ca2+ influx across an unstable sarcolemma due to increased activity of a STIM1-Orai1 complex is a disease determinant in muscular dystrophy, and hence, SOCE represents a potential therapeutic target.