Clefts of the lip, alveolus, and/or palate, which are called orofacial clefts (OFC), occur in 0.5 to 3 per 1000 live and stillbirths. The pathogenesis of these congenital malformations remains largely unknown, but evidence is increasing that both nutritional and genetic factors are involved. Unlike genetic factors, nutritional causes can be corrected and may therefore contribute to the prevention of OFC. The goal of this review is to summarize the embryogenesis and genes involved in OFC, and to give an overview of the nutrients and related genes in humans. Improving our knowledge of the role of nutrition, genes, and their interactions in the pathogenesis of OFC may stimulate the development of nutritional interventions for OFC prevention in the future.