Neural crest cells are a vertebrate innovation and form a wide variety of embryonic cell types as diverse as peripheral neurons and facial skeleton. They undergo complex migration and differentiation processes from their site of origin in the developing central nervous system to their final destinations in the periphery. In this review, we summarize recent data on the current formulation of a gene regulatory network underlying neural crest formation and its roots at the base of the vertebrate lineage. Analyzing neural crest formation from a gene regulatory viewpoint provides insights into both the developmental mechanisms and evolutionary origins of this vertebrate-specific cell type.