The complex processes of initiation and coordination of signaling between the central nervous system (CNS) and muscles are highly susceptible to damage in neuromuscular disease (NMD). This vulnerability is positioned most prominently at the neuromuscular junction (NMJ), where motor neurons generate muscle contraction by releasing acetylcholine into the synaptic cleft. Sadly, partially due to a lack of complete scientific understanding of the human NMJ, there is currently no cure for NMDs characterized by dysfunctional NMJs. While the cellular and molecular features of mouse NMJs have been characterized in depth, there is much less known about the human NMJ. Thus, it is not surprising that drugs found to alleviate symptoms in NMD animal models by acting at the NMJ have frequently failed in clinical trials. In order to expand our understanding in ways that will lead to effective treatments for patients, the field needs to move beyond animal models and directly study human NMJs. I propose to address this unmet need by modeling NMD-related NMJ dysfunction with human cells from patients. I hypothesize that this approach will identify novel targets and pathways, thereby establishing a platform for the discovery of drugs that will effectively treat human NMDs.