The advent of genome editing technologies, including the RNA-guided CRISPR/Cas9 system, has enabled the precise editing of endogenous human genes. We have applied these tools to the correction of mutations that cause genetic disease. For example, we engineered CRISPR/Cas9-based nucleases to correct the human dystrophin gene that is mutated in Duchenne muscular dystrophy patients. When we delivered these nucleases to cells from patients with this disease, the correct gene reading frame and expression of the functional dystrophin protein were restored in vitro and following cell transplantation into mouse models in vivo (Ousterout et al., Nature Communications 2015). When delivered directly to a mouse model of this disease, gene editing by the CRISPR/Cas9 system led to gene restoration and improvement of biochemical and mechanical muscle function (Nelson et al., Science 2016). In more recent studies we have shown that genome editing and dystrophin protein restoration is sustained in the mdx mouse model of DMD for one year after a single intravenous administration of AAV-CRISPR. We also confirmed immunogenic host response to Cas9 when administered via AAV vectors to adult mice, but show that the humoral and cellular immune response can be avoided by treating neonatal mice (Nelson et al., Nature Medicine 2019). Additionally, we have observed unintended genome and transcript alterations induced by AAV-CRISPR that should be considered for the development of AAV-CRISPR as a therapeutic approach. More recently, we have developed novel animal models of this disease for the preclinical development of therapies that will correct human disease-causing mutations. New constructs have been developed and validated for significant levels of gene correction and dystrophin restoration in this model. We have also confirmed in vivo editing of satellite cells, the stem cells of skeletal muscle that participate in muscle regeneration. These studies demonstrate the potential for genome editing to be used to treat Duchenne muscular dystrophy and other neuromuscular disorders, and also highlight aspects of host response and alternative genome editing outcomes for further study.