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Many muscular dystrophies, including lethal Duchenne muscular dystrophy, are incurable and require the sustained application of drugs that have only minor treatment effects and serious negative side effects. The mechanism of siRNA-mediated transcriptional gene regulation (TGR) appears to have a long-lasting effect and may be a viable solution to treat muscle disorders because single or at least rarely repeated therapies would be used. For the best results, siRNA should be delivered to all disease affected muscles, and systemic delivery of siRNA through blood vessels is probably the only applicable choice to achieve this goal. Unfortunately, there are many challenges to overcome such as siRNA degradation in blood, renal clearance, blood–muscle barrier, cell entry and endosomal escape. By exploiting and considering the unique features of muscles and the mechanism of TGR, we will discuss the possible ways to induce TGR in muscles by using non-viral systemic siRNA delivery methods.