Muscular dystrophies are genetically diverse disorders clinically characterized by progressive weakness of muscles of limbs, cranium, or both and by histologic degeneration and regeneration of muscle without abnormal storage of metabolic products. Advances in molecular genetics have revolutionized our understanding of muscular dystrophies, beginning in 1987 with the identification of mutations leading to dystrophin deficiency in Duchenne's muscular dystrophy [1]. Since then, at least 20 genetically distinct forms of limb-girdle muscular dystrophy (LGMD) have been identified [2]. Four subtypes of autosomal recessive LMGD are the result of mutations in genes encoding sarcoglycans (SGs) α, β, γ, and δ, which form a subcomplex of the dystrophin–glycoprotein complex linked to muscle membranes. The LGMD variants due to SG mutations are LGMD2C (δ-SG), LGME2D (α-SG), LGMD2E (β-SG), and LGMD2F (γ-SG) [3]. Although molecular genetics has been a powerful tool in unraveling the pathogenesis of muscular dystrophies, harnessing the therapeutic potential of molecular biology for these devastating muscle diseases has been technically challenging. For autosomal recessive diseases with loss of functional protein (e.g., sarcoglycanopathies and dystrophinopathy), gene replacement therapy is a promising approach. Viral delivery of genes was first performed successfully in children with severe combined immunodeficiency by using retroviruses to deliver normal genes to the patients' bone marrow stem cells, which were removed from the children, infected with the virus (tranduced), and injected into the bloodstream, where they engrafted and restored normal immune cells [4, 5]. Unfortunately, 5 of 20 children treated with retroviral gene therapy developed leukemias because vector insertion into the patients' DNA activated an oncogene, thus exposing one of the potential pitfalls of gene therapy [6]. Other technical obstacles to gene therapy include inefficient gene delivery, immune rejection, and other vector toxicities. To develop gene therapy for muscular dystrophy, viral and nonviral vectors have been used to deliver genes in experimental cellular and animal models [7]. Adeno-associated viruses (AAVs) are promising viral vectors for gene delivery because they are not known to cause human disease; however, AAVs have a small DNA-carrying capacity and therefore cannot be used to carry large genes such as dystrophin. In contrast, the α-SG gene (SGCA) is relatively small and can be packaged into AAVs; therefore, AAV delivery of SGCA to patients with LGMD2D is a potentially achievable goal that Mendell and colleagues are pursuing.