Muscular dystrophies are commonly associated with progressive loss of muscle mass and strength as a consequence of ongoing myofibril degeneration and wasting. Genetic therapies have been proposed as interventions for disorders where specific monogenic mutations have been linked to the origin of disease. For muscular dystrophies of this nature, a single-gene therapy intended to introduce a surrogate gene in lieu of the defective endogenous copy (or to ablate a dominant negative state) may prove sufficient to prevent or reverse the development of disease. However, the increasingly severe morphological disruption and depletion of functional muscle fibers observed with disease progression may prove to be difficult to halt or reverse completely depending on the severity of the condition at the time of treatment. Consequently, it may be advantageous to consider coadministration of additional genetic interventions that address not only primary genetic defect, but also exert beneficial effects via other means that minimize degeneration, enhance muscle function, and promote muscle regeneration. Using Duchenne muscular dystrophy (DMD) as a representative neuromuscular condition, this chapter will discuss the potential benefits of combining genetic interventions to prevent or reverse the loss of muscle function, and also treat the primary genetic defect.