Duchenne muscular dystrophy is a devastating inherited neuromuscular disorder that affects one in 3300 live male births. Although the responsible gene and its product, dystrophin, have been characterized for more than 15 years, and a mouse model (mdx) has been developed, comprehensive understanding of the mechanism leading from the absence of dystrophin to the muscular degeneration is still debated. First, dystrophin is considered a key structural element in the muscle fiber, and the primary function of the dystrophin-associated protein complex is to stabilize plasma membrane, although a role of signaling is still possible. Mechanically induced damage through eccentric contractions puts a high stress on fragile membranes and provokes micro-lesions that could eventually lead to loss of calcium homeostasis, and cell death. Altered regeneration, inflammation, impaired vascular adaptation, and fibrosis are probably downstream events that take part in the muscular dystrophy and that probably vary a lot along species (i.e., mdx mice), probands within families, stressing the importance of epigenic factors. Because no etiologic therapy is available for Duchenne muscular dystrophy, a better understanding of the primary and downstream mechanisms could prove useful for producing new adjuvant treatments. All pathophysiologic mechanisms are reviewed together with perspectives on management.