Because of its unique ability to generate a wide variety of both neural and nonneural derivatives, the neural crest is an ideal model system to study the factors regulating cell lineage decisions in stem and progenitor cells. The use of various cell culture techniques and in vivo functional assays, including cell type-specific gene manipulation in mouse, helped to identify signaling factors involved in this process. Moreover, it became apparent that the biological functions of growth factors acting on neural crest cells depend on the context provided by the extracellular microenvironment. Thus, signaling molecules have to be viewed as parts of complex networks that change with time and location. Neural crest cells have to integrate these signals to ensure the generation of appropriate numbers of differentiating progeny. It will be important to determine how such signaling networks are established and how they elicit multiple signaling responses in neural crest cells to activate appropriate genetic programs.