Fate segregation of multipotent progenitors is a key developmental process. The neural crest, which generates numerous cell types, is an ideal system in which to investigate this process. On p. 2269, Chaya Kalcheim and co-workers investigate when and how neurogenic and melanogenic neural crest cells segregate. Previously, the researchers reported that, even before emigration from the neural tube, neural but not melanocyte progenitors express the transcription factors Foxd3, Sox9 and Snail2. Now, they show that avian melanocytes are initially part of the Foxd3-positive premigratory epithelium but downregulate Foxd3 before emigration from the neural tube. If Foxd3 downregulation is prevented, avian melanocyte progenitors fail to upregulate the melanogenic marker Mitf and the guidance receptor Ednrb2. Consistent with these data, loss of Foxd3 function in mouse neural crest results in ectopic melanogenesis in the dorsal tube and sensory ganglia. The researchers propose, therefore, that Foxd3 is part of a dynamically expressed network of neural tube genes that regulates the segregation of neurogenic and melanogenic neural crest cells.