Clefts of the lip and palate are a common craniofacial anomaly, requiring complex multidisciplinary treatment and having lifelong implications for affected individuals. The aetiology of both cleft lip with or without cleft palate (CLP) and isolated cleft palate (CP) is thought to be multifactorial, with both genetic and environmental factors playing a role. In recent years, a number of significant breakthroughs have occurred with respect to the genetics of these conditions, in particular, characterization of the underlying gene defects associated with several important clefting syndromes. These include the identification of mutations in the interferon regulatory factor-6 (IRF6) gene as the cause of van der Woude syndrome and the poliovirus receptor related-1 (PVRL1) gene as being responsible for an autosomal recessive ectodermal dysplasia syndrome associated with clefting. While no specific disease-causing gene mutations have been identified in non-syndromic clefting, a number of candidate genes have been isolated through both linkage and association studies. However, it is clear that environmental factors also play a role and an important area of future research will be to unravel interactions that occur between candidate genes and environmental factors during early development of the embryo. Orthodontists are intimately involved in the therapeutic management of individuals affected by CLP and it is important that they keep abreast of current knowledge of the aetiology behind these conditions. This review aims to summarize some of the more significant advances in the genetics of CLP and highlight current thinking on the modes of inheritance and genetic loci that might be involved in this complex disorder.