Objective: Genetics has been thought to play a crucial role in the etiology of nonsyndromic cleft lip and palate (CL/P) for over 60 years, but we are still no closer to finding contributing genes. The main hindrance to the progress of CL/P genetic research is the complex multifactorial nature of the disorder with environmental factors playing a significant, if not equally important role. Thus, CL/P is the likely outcome of several developmental and biochemical events that may be different in different individuals or families. Conclusions: Because of the known advantages of folate therapy during pregnancy and the developmental problems that may occur when diets are folate deficient, recent research has looked toward a possible genetic explanation for susceptibility to low folate status. Several gene variants have been identified which, when combined with an inadequate diet, may impede human development, but it still remains to be seen whether these are a major contributor to CL/P. Here we review some of the current viewpoints and the possible impact of folic acid supplementation on clefting incidence.