Cleft palate is among the most common major birth defects. In the United States and Europe, cleft palate occurs in approximately 6/10,000 births. However, there are regions of the world where the prevalence of cleft palate is higher, as well as regions where the prevalence is lower. In addition to regional variations, the prevalence of cleft palate varies by race and ethnicity and is higher in females than in males. The risk that a child will be born with cleft palate is influenced by both genetic and environmental risk factors, with the latter broadly including maternal conditions, nutrition, substance use, and exposures in the home and workplace. Established risk factors for cleft palate include maternal pregestational diabetes, periconceptional smoking, and the use of certain medications. Other factors that have been associated with an increased risk of cleft palate include maternal prepregnancy obesity, diabetes that develops during pregnancy, and the use of artificial reproductive technologies. There is also evidence that maternal, periconceptional use of folic acid-containing supplements may reduce the risk of having a child with cleft palate. However, as the known risk factors do not fully account for the population burden of cleft palate, continued research is needed to further our understanding of this condition.