Over 700 heritable diseases are associated with defects in skeletal muscle function, and musculoskeletal diseases can have a devastating impact on life expectancy and quality of life. Although the mechanisms of muscle development and homeostasis have been intensely studied for decades, the underlying causes of some musculoskeletal disorders are unknown. We hypothesized that unbiased genetic screens would uncover new regulators of muscle function, and we used the powerful forward genetic tools in fruit flies to identify dozens of genes that control muscle development. These studies ultimately led to us to sequence and study mutations in patients, which in turn identified new pathogenic mechanisms that affect skeletal muscle function. Unfortunately fruit flies do not mount a robust regenerative response to muscle injury, so we developed an inducible injury platform in zebrafish that is amenable to forward genetic screens and organism-wide transcriptomics. We found muscle regeneration is regulated by distinct mechanisms along the body axes, suggesting progressive muscle diseases may preferentially target specific muscles based on anatomical position. In summary, our gene hunts are identifying new regulators of muscle development, disease, and regeneration.