The use of recombinant adeno-associated viruses (rAAVs) is highly prevalent in musculoskeletal gene therapies due to their versatility, high transduction efficiency, natural tropism and vector genome persistence for years. As the largest organ in the body, treatment of skeletal muscle for widespread and sufficient therapeutic gene expression is highly challenging. In addition to disease-specific hurdles, vector genome loss, off-target gene transfer and immune responses to treatment can diminish the overall benefit of rAAV therapies. A variety of approaches have been developed to overcome these challenges and improve musculoskeletal targeting of rAAVs. This review focuses on recent advancements and remaining obstacles in creating optimal rAAV-based therapies for musculoskeletal application.