First few pages of this chapter are devoted to the description of molecular regulation of the normal embryological development of the palate. The role of Shh, BMP 2/4, TGF-B3 and Msx-1 genes in the development of palate is described at length. The population based studies have shown that 50 to 70% of cleft lip/cleft palate births had no other major malformation while upto 30% are associated with other anomalies. 10 to 15% of all cleft lip/palate cases report a positive family history. The etiology of CL/P is complex and thought to involve genetic influences with variable interactions from environmental factors. However, overall environmental factors are considered much less important agents than genetic factors in the etiology of oral clefts. Genetic causes of oral clefting include syndromic and non-syndromic. In syndromic form the cleft is always associated with other malformations. Usually it is due to single gene involvement (monogenic or Mendelian). Over 300 syndromes are known to be associated with cleft lip or palate as an associated feature. In non-syndromic form the cleft is mostly an isolated feature. It is said to be polygenic in nature. It is produced out of interaction between a number of genes; each producing a small effect that add up together to produce the clefting. It has been observed that some of the genes that are responsible for causing syndromic forms of clefting are also responsible for causing non-syndromic form of clefting. These overlapping genes are MSX-1, IRF6, PVRL 1, CATCH 22, TGF B3 and TBX 22.