Mutations that disrupt the dystrophin glycoprotein complex lead to plasma membrane instability of cardiomyocytes and skeletal muscle myofibers. Instability of the plasma membrane leads to degeneration largely due to activation of a necrotic process in these disorders. In response to ongoing degeneration, skeletal muscle exhibits robust regeneration while in cardiac muscle regeneration is not obvious. The dystrophin complex is concentrated along the plasma membrane in costameric structures that correspond to the Z bands of sarcomeres, thus positioning the dystrophin complex to transmit force between the sarcomere and the plasma membrane to the extracellular matrix. Although it is apparent that this position is important for perpendicular force transmission, it is clear that the dystrophin complex also fulfills signaling roles. Nitric oxide synthase and stress-induced signaling cascades are activated to participate in protection but may also contribute to pathology.