Advances in next-generation sequencing have transformed our ability to identify genetic variants associated with clinical disorders of the musculoskeletal system. However, the means to functionally validate and analyze the physiological repercussions of genetic variation have lagged behind the rate of genetic discovery. The zebrafish provides an efficient model to leverage genetic analysis in an in vivo context. Its utility for orthopedic research is becoming evident in regard to both candidate gene validation as well as therapeutic discovery in tissues such as bone, tendon, muscle, and cartilage. With the development of new genetic and analytical tools to better assay aspects of skeletal tissue morphology, mineralization, composition, and biomechanics, researchers are emboldened to systematically approach how the skeleton develops and to identify the root causes, and potential treatments, of skeletal disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:925-936, 2020.
