This review considers the most significant progress in developing genetic therapeutic interventions for Duchenne muscular dystrophy (DMD), in order to illustrate the challenges facing gene therapy of all the muscular dystrophies (MDs). While in vivo repair of genetic mutations affecting muscle remains inefficient, the most promising interventions focus on supplementation of minimally sized transgenes encoding the abnormal muscle proteins. Intramuscular injection of recombinant viral vectors carrying therapeutic transgenes has yielded the most impressive amelioration of dystrophic muscle pathology in animal models, although achieving lasting, body-wide transgene delivery in the absence of a significant immunological reaction remains unrealised. Ex vivo correction and engraftment of muscle precursor and stem cell populations remains a potential (albeit presently less efficient) alternative to in vivo interventions. Recent advances provide encouraging evidence for the feasibility of genetic therapy of the MDs, but further evaluation of interventions in larger animal models and ultimately human trials is necessary to identify the most promising techniques for development.