Cyclopia, the paradigmatic “face [that] predicts the brain” in severe holoprosencephaly (HPE) (DeMyer et al., 1964), has been recognized since ancient times. Descriptive embryologists and pathologists have noted the continuum of defective separation of the forebrain and loss of central nervous system (CNS) mid‐line structures for more than a century. It has been recognized more recently that inhibitors of cholesterol biosynthesis, whether consumed in native plants by range sheep, or experimentally applied to early embryos, could pheno‐copy the natural malformation, as could a variety of other teratogens (maternal diabetes, alcohol). Yet it has been less than a decade that the genomic knowledge base and powerful analytic methods have brought the sciences of descriptive, molecular, and genetic embryology within range of each other. In this review, we discuss the clinical presentations and pathogenesis of HPE. We will outline various genetic and teratogenic mechanisms leading to HPE. Lastly, we will attempt to examine the pivotal role of cholesterol and the Sonic Hedgehog (Shh) pathway in this disorder and in normal embryonic forebrain development.