Many maternal risk factors have been implicated in the development of non-syndromic cleft lip and/or palate (CLP), including high BMI, smoking, alcohol, anticonvulsant use, vitamin B6 and folic acid levels. An increasing body of literature also suggests a role for epigenetics in regulating orofacial development. However, it is unclear whether identified maternal risk factors are causally associated with CLP or confounded by other factors, and human data on the epigenetics of CLP are lacking. Clarification of the true, causal risk factors for CLP and the biological processes through which they exert their effects will help advise preventative strategies to lower CLP incidence.