The muscular dystrophies are progressive disorders of striated muscle leading to breakdown of muscle integrity. Underlying this clinical presentation there is considerable genetic heterogeneity with the X-chromosomal recessive Duchenne and Becker forms comprising the majority of patients, and the related limb girdle muscular dystrophies (LGMD) being caused by an additional 10 different genetic loci. Much has been learned over the last 12 years about the molecular defects associated with the muscular dystrophies, beginning with the identification of dystrophin as the protein altered in Duchenne/Becker muscular dystrophy. Dystrophin has since been shown to be part of a complex of proteins at the muscle cell membrane known as the dystrophin associated protein (DAP) complex. Five other protein members of this complex are themselves encoded by genes that are disrupted in LGMD patients. The exact mechanism by which the muscle cell undergoes degeneration when this complex is disturbed is unknown. To date there is no known way to halt the muscle cell degeneration when this complex is perturbed, although animal studies have shown that introduction of the normal gene into diseased muscle is corrective for the problem. We continue our two broad areas of research to address the pathogenesis and treatment of the muscular dystrophies. The first is a continuation of our efforts to unravel the normal function of the dystrophin associated protein complex and why alteration of genes encoding members of the complex causes the phenotype of muscular dystrophy. The second is our continuing effort to develop a stem cell-based therapy for treatment of patients with muscular dystrophy. Both broad areas are driven by our hope to be curative for the muscular dystrophies.