This review has focused on only two common structural malformations. However, the difficulties and successes encountered while attempting to elucidate the genetic contribution to these two conditions are likely to be echoed in studies of other complex congenital anomalies. As our understanding of the mechanisms which give rise to a particular malformation gradually unfolds, the importance of a multidisciplinary approach to understanding the genetic contribution to these conditions becomes increasingly apparent. Experience indicates that both traditional and genetic epidemiologic approaches will be integral components of any such efforts, since the identification of environmental risk factors (e.g., folic acid) may provide clues regarding the nature of disease susceptibility loci, and the identification of susceptibility loci will provide new opportunities to explore potential environmental covariates of disease risk (e.g., maternal cigarette smoke). Although we are not yet in a position to completely describe the genetic contribution to any single structural malformation, advances over the past decade have led to a rapid increase in our ability to elucidate the relevant genetic factors. Given the complex nature of the nonsyndromic structural malformations, there is undoubtedly much work to be done before we fully understand the genetic contribution to even a single malformation. However, for the first time, such an understanding and the accompanying potential for prevention seem within our reach.