Holoprosencephaly is a relatively rare malformation of the central nervous system (CNS) that is frequently associated with specific craniofacial anomalies including midline facial clefts, cyclopia, and nasal anomalies. The incidence in live born children with normal chromosomes has been estimated to be 0.48-0.88 per 10,000 (1-3). In contrast, the rate among human abortuses was estimated at 40 per 10,000 indicating a high rate of fetal loss (4). Until recently, the pathogenesis of this disorder remained speculative, however, advances over the past 10 years have provided a clearer picture of the development of this anomaly in at least some cases. This review provides an update of the current data regarding predisposing factors, genetics, and pathology of holoprosencephaly. Finally, the cellular and molecular basis underlying the development of holoprosencephaly will be considered. These data support the hypothesis that early induction and patterning of the neural tube is essential for normal development, and disruptions in this patterning result in CNS malformations.