There are two principal models to explain neural crest patterning. One assumes that neural crest cells are multipotent precursors that migrate throughout the embryo and differentiate according to cues present in the local environment. A second proposes that the neural crest is a population of cells that becomes restricted to particular fates early in its existence and migrates along particular pathways dependent on unique cell-autonomous properties. Although it is now evident that the neural crest cell population, as a whole, is actually heterogenous (composed of both multipotent and restricted progenitors), evidence supporting the model of prespecification has increased over the past few years. This review will begin by telling the story of melanoblasts: a neural crest subpopulation that is biased toward a single fate and subsequently acquires intrinsic properties that guide cells of this lineage to their final destination. The remainder of this review will explore whether this model is exclusive to melanoblasts or if it can also be used to explain the patterning of other neural crest cells like those of the sensory, sympathoadrenal, and enteric lineages. Developmental Dynamics 236:1–19, 2007. © 2006 Wiley-Liss, Inc.