The combined experimental attributes of the zebrafish model system, which accommodates cellular, molecular, and genetic approaches, make it particularly well-suited for determining the mechanisms underlying normal vertebrate development as well as disease states, such as cancer. In this chapter, we describe the advantages of the zebrafish system for identifying genes and their functions that participate in the regulation of the development of the peripheral sympathetic nervous system (PSNS). The zebrafish model is a powerful system for identifying new genes and pathways that regulate PSNS development, which can then be used to genetically dissect PSNS developmental processes, such as tissue size and cell numbers, which in the past haves proved difficult to study by mutational analysis in vivo. We provide a brief review of our current understanding of genetic pathways important in PSNS development, the rationale for developing a zebrafish model, and the current knowledge of zebrafish PSNS development. Finally, we postulate that knowledge of the genes responsible for normal PSNS development in the zebrafish will help in the identification of molecular pathways that are dysfunctional in neuroblastoma, a highly malignant cancer of the PSNS.