AAV-mediated gene therapy has emerged as a promising approach for treating skeletal diseases, offering sustained gene expression with low immunogenicity and pathogenicity. Preclinical studies support its therapeutic efficacy and safety, with emerging strategies such as gene addition, replacement, silencing, and editing showing potential for clinical application. AAV vectors are particularly effective for targeting bone tissue, with preclinical studies demonstrating their ability to treat rare diseases like fibrodysplasia ossificans progressiva (FOP) and osteogenesis imperfecta (OI), as well as prevalent conditions such as osteoporosis, osteoarthritis, and bone fractures. Despite challenges like high cost, safety concerns, and limited cargo capacity, AAV-based gene therapy remains a promising platform for delivering therapeutic genes to the skeleton. AAV vectors have a favorable safety profile, high transfection efficiency, and the ability to target specific tissues, making them suitable for long-term treatment of skeletal disorders. However, limitations such as size constraints, preexisting immunity, and the need for precise targeting remain significant challenges. Advances in AAV vector design, capsid engineering, and gene editing technologies are improving transduction efficiency, specificity, and safety. Preclinical studies have shown promising results in treating various skeletal diseases, including FOP, MPS-IVA, and OI, with AAV-mediated gene therapy offering a potential alternative to conventional treatments. Despite these advancements, further research is needed to address the challenges and optimize AAV-based gene therapy for clinical translation.AAV-mediated gene therapy has emerged as a promising approach for treating skeletal diseases, offering sustained gene expression with low immunogenicity and pathogenicity. Preclinical studies support its therapeutic efficacy and safety, with emerging strategies such as gene addition, replacement, silencing, and editing showing potential for clinical application. AAV vectors are particularly effective for targeting bone tissue, with preclinical studies demonstrating their ability to treat rare diseases like fibrodysplasia ossificans progressiva (FOP) and osteogenesis imperfecta (OI), as well as prevalent conditions such as osteoporosis, osteoarthritis, and bone fractures. Despite challenges like high cost, safety concerns, and limited cargo capacity, AAV-based gene therapy remains a promising platform for delivering therapeutic genes to the skeleton. AAV vectors have a favorable safety profile, high transfection efficiency, and the ability to target specific tissues, making them suitable for long-term treatment of skeletal disorders. However, limitations such as size constraints, preexisting immunity, and the need for precise targeting remain significant challenges. Advances in AAV vector design, capsid engineering, and gene editing technologies are improving transduction efficiency, specificity, and safety. Preclinical studies have shown promising results in treating various skeletal diseases, including FOP, MPS-IVA, and OI, with AAV-mediated gene therapy offering a potential alternative to conventional treatments. Despite these advancements, further research is needed to address the challenges and optimize AAV-based gene therapy for clinical translation.