Sarcoglycan is a multimeric, integral membrane glycoprotein complex that associates with dystrophin. Mutations in individual sarcoglycan subunits have been identified in inherited forms of muscular dystrophy. To evaluate the contributions of sarcoglycan and dystrophin to muscle membrane stability and muscular dystrophy, we compared muscle lacking specific sarcoglycans or dystrophin. Here we report that mice lacking δ-sarcoglycan developed muscular dystrophy and cardiomyopathy similar to mice lacking γ-sarcoglycan. However, unlike muscle lacking γ-sarcoglycan, δ-sarcoglycan-deficient muscle was sensitive to eccentric contraction-induced disruption of the plasma membrane. In the absence of δ-sarcoglycan, α-, β- and γ-sarcoglycan were undetectable, while dystrophin was expressed at normal levels. In contrast, without γ-sarcoglycan, reduced levels of α-, β- and δ-sarcoglycan were expressed, glycosylated and formed a complex with each other. Thus, the elimination of γ- and δ-sarcoglycan had different molecular consequences for the assembly and function of the dystrophin-glycoprotein complex. Furthermore, these molecular differences were associated with different mechanical consequences for the muscle plasma membrane. Through this in vivo analysis, a model for sarcoglycan assembly is proposed.