Musculoskeletal conditions are a major public health problem. Approximately 66 million individuals seek medical attention for a musculoskeletal injury in the United States, with current medical costs being estimated at $873 billion annually. Despite advances in pharmaceuticals, implant materials and surgical techniques, there remains an unmet clinical need for successful treatment of challenging musculoskeletal injuries and pathologic conditions, particularly in the setting of compromised biological environments. Tissue engineering via gene therapy attempts to provide an alternative treatment strategy to address the deficits associated with conventional approaches. The transfer of specific target genes coding for proteins with therapeutic or regenerative properties to target cells and tissues in the disease environment allows for their sustained production and release specifically at the site of interest. The increasing reports of success with gene therapy-based treatments in the clinical management of a variety of diseases provide genuine optimism that similar methods can be adapted for mainstream clinical application in musculoskeletal disorders. In preclinical studies, gene therapy has been successfully used to treat cartilaginous, bone, skeletal muscle, tendon, ligament and intervertebral disk injuries. In addition, gene therapy is being assessed in clinical trials for its safety and therapeutic potential in osteoarthritis. This review will specifically address the clinical potential, preclinical data and future hurdles for gene therapy to be a viable clinical entity for the treatment of fracture nonunion and difficult bone repair scenarios, articular cartilage repair and osteoarthritis.