Nemaline Myopathy is a genetically and clinically heterogeneous group of neuromuscular disorder most commonly presenting with congenital/childhood-onset hypotonia and muscle weakness. Despite the substantial progress in uncovering the genetics of these disorders, there is still no specific treatment available due to a lack of understanding of the origin and progression of pathophysiological processes contributing to the disease state. Mutations in Kelch proteins encoding genes are associated with recessive and dominant rare forms of nemaline myopathy (Kelch-NM). We have recently created zebrafish and mouse models of NM causing Kelch genes that recapitulate the clinical and pathological defects associated with NM patients. Using in vivo proteomics and imaging approaches, we have identified critical roles of NM causing Kelch genes in sarcomere development, maintenance, and cellular trafficking. These studies reveal the mechanism of muscle abnormalities in nemaline myopathy and provide insights into new pathways regulating normal and disease muscle. Finally, using gene targeting and small molecules-based screening approaches in Kelch-NM animal models, we aim to develop therapeutics for NM and related muscle disorders.