Nonsyndromic cleft lip and/or palate (or orofacial cleft, OFC) is a malformation characterized by an incomplete separation between nasal and oral cavities without any associated anomalies. The last point defines the distinction between syndromic and nonsyndromic OFC. Nonsyndromic OFC is one of the most common malformations among live births and is composed of two separate entities: cleft lip with or without cleft palate (CL+/-P) and cleft palate isolated (CPI). Because of the complex etiology of nonsyndromic OFC, which is due to the differences between CL+/-P and CPI, and the heterogeneity of each group, caused by the number of genes involved, the type of inheritance, and the interaction with environmental factors, we reviewed those genes and available loci in the literature whose involvement in the onset of nonsyndromic OFC has more sound scientific evidence. Genetic studies on human populations have demonstrated that CL+/-P and CPI have distinct genetic backgrounds and, therefore, environmental factors probably disclose only these malformations. In CL+/-P several loci, OFC from 1 to 10 have been identified. The first locus, OFC1, has been mapped to chromosome 6p24. Other CL+/-P loci have been mapped to 2p13 (OFC2), 19q13.2 (OFC3) and 4q (OFC4). OFC5-8 are identified by mutations in the MSX1, IRF6, PVRL1, and TP73L gene, respectively. OFC9 maps to 13q33.1-q34, whereas OFC10 is associated with haploinsufficiency of the SUMO1 gene. In addition, MTHFR, TGF-beta3, and RARalpha play a role in cleft onset. In CPI one gene has been identified (TBX22) at present, but others are probably involved. Greater efforts are necessary in order to have a complete picture of the main factors involved in lip and palate formation. These elements will permit us to better understand and better treat patients affected by OFC.