Orofacial clefts are the most common craniofacial birth defects and one of the most common congenital malformations in humans. They require complex multidisciplinary treatment and are associated with elevated infant mortality and significant lifelong morbidity. The development of craniofacial structures is an exquisitely orchestrated process involving the coordinated growth of multiple, independently derived primordia. Perturbations impacting on the genesis or growth of these primordia may interfere with the proper morphogenesis of facial structures, resulting in clefting of the lip, the primary or secondary palate, or a combination of these sites. A variety of genetic approaches involving both human populations and animal models have greatly facilitated the search for genes involved in human clefting. In this article, we review the most prominent genes for orofacial clefts in the context of developmental pathways that shape the craniofacial complex. We highlight several Mendelian clefting syndromes that have provided valuable clues in identifying genes for the more common, isolated forms of clefting. Finally, we elaborate on a number of potential subclinical features (subphenotypes) associated with what have previously been diagnosed as ‘isolated’ clefts that may serve as additional markers for identifying individuals or families in whom there may be a greater risk of inheriting a cleft.