The neural crest is a transient population of migratory cells in the embryo that gives rise to a wide variety of different cell types, including those of the peripheral nervous system. Dysfunction of neural crest cells (NCCs) is associated with multiple diseases, such as neuroblastoma and Hirschsprung disease. Recent studies have identified NCC behaviors during their migration and differentiation, with implications for their contributions to development and disease. Here, we describe how interactions between cells of the neural crest and lineages such as the vascular system, as well as those involving environmental signals and microbial pathogens, are critically important in determining the roles played by these cells.