Since its first description in 1990, the dystrophin-glycoprotein complex has emerged as a critical nexus for human muscular dystrophies arising from defects in a variety of distinct genes. Studies in mammals widely support a primary role for the dystrophin-glycoprotein complex in mechanical stabilization of the plasma membrane in striated muscle and provide hints for secondary functions in organizing molecules involved in cellular signaling. Studies in model organisms confirm the importance of the dystrophin-glycoprotein complex for muscle cell viability and have provided new leads toward a full understanding of its secondary roles in muscle biology.