Wolf-Hirschhorn Syndrome (WHS) is a neurodevelopmental disorder characterized by mental retardation, craniofacial malformation, and defects in skeletal and heart development. The syndrome is associated with irregularities on the short arm of chromosome 4, including deletions of varying sizes and microduplications. Many of these genotypic aberrations in humans have been correlated with the classic WHS phenotype, and animal models have provided a context for mapping these genetic irregularities to specific phenotypes; however, there remains a significant knowledge gap concerning the cell biological mechanisms underlying these phenotypes. This review summarizes literature that has made recent contributions to this topic, drawing from the vast body of knowledge detailing the genetic particularities of the disorder and the more limited pool of information on its cell biology. Finally, we propose a novel characterization for WHS as a pathophysiology owing in part to defects in neural crest cell motility and migration during development.