In line with a prominent role for SHH in forebrain development, defects in SHH signaling in humans (Roessler et al., 1996) and in mouse models (Chiang et al., 1996) result in midline formation defects, ultimately causing craniofacial malformation and holoprosencephaly (HPE). The gene discussed is SHH; the disease is holoprosencephaly.