We have seen that what must be applied to dysmorphology is the doctrine of multifactorial causality, ie dysmorphogenetic events have both genetic and nongenetic etiologic components to varying degrees. Complicating matters is the extent to which there is etiologic and/or mechanistic heterogeneity (Fig. 1). This is nicely illustrated by the holoprosencephaly anomaly. In addition, there are numerous CNS malformations that have major single gene, chromosomal, or environmental initiating agents of malformation mechanisms. Still a mystery is the common neural tube malformations. It is now clear that the "multifactorial/threshold" model is an inadequate explanation of the observed data and until the etiologic heterogeneity of these malformations is clearly defined, our knowledge remains primarily empiric. A potential area of fruitful investigation is likely to be the identification of maternal genotypes which do not allow detoxification of potential environmental teratogens.