Nonsyndromic cleft of the lip with or without palate (CLP) derives from an embryopathy with failure of the nasal processes and / or fusion of the palatal shelves. This severe birth defect is one of the most common malformations among live births. Human cleft is composed of two separate entities: cleft lip and / or palate (CLP) and cleft palate only (CPO). Both have a genetic origin, whereas environmental factors contribute to these congenital malformations. In this review we analyse the role of drugs, environmental factors, genes and loci related to the onset of cleft. The data were obtained from (i) epidemiologic studies, (ii) animal models and (iii) human genetic investigations. Epidemiologic studies have demonstrated a relation between certain environmental factors (alcohol, cigarette smoking, steroids and anticonvulsants) during pregnancy and a higher risk of generating offspring with CLP. On the contrary, folic acid intake seems to have a protective effect. No clear relation has been demonstrated between aspirin and CLP. Murine models were developed to investigate drug-induced embryopathy and, more recently, to obtain information regarding genes and biochemical pathways. Steroids and anticonvulsants are the most widely studied clefting drugs, whereas TGFs and retinoic acids are the most thoroughly investigated among biochemical pathways. Human genetic studies on CLP have identified several loci and, in one case, also a specific gene. In CPO, one gene has been identified, though many more are probably involved. Among the identified chromosomal regions, there are some carrying genes with functions related to environmental factors with a clefting or protective effect.