The potential usefulness of viral gene replacement therapy in human disease has been an exciting and extensively-studied topic in the field of skeletal muscle disease for the past 20 years. Unfortunately, while the strategy of replacing or supplementing copies of mutant gene is a straightforward concept, a number of complicating factors have been identified as gene therapy trials have progressed toward clinical studies. While some of these issues, including the immunological response to viral vectors, are issues that are encountered with all forms of gene therapy, the use of gene therapy in skeletal muscle also poses additional challenges for which treatment strategies need to be optimized. Despite these challenges, there has been substantial progress in recent years toward optimizing viral gene therapy for skeletal muscle disease in animal models, with an eye toward optimizing the safety and efficacy of viral gene therapy in humans.