Purpose: The purpose of this study was to evaluate the Biological Mechanisms of Lithium separately and in combination with Caffeine in Palatogenesis in Albino Rat Materials and Methods: Thirty six adult rats were used in this study, twenty four female and twelve male rats, after mating procedures and confirmation of pregnancy the pregnant rats were divided into 3 groups :group1(control) , which consists of six pregnant rats and were not receive any medication during gestation, group2' Which consists of nine pregnant rats and were received prianil (lithium carbonate) 200mg/kg intragasteric During the period of ( 6th to 15th ) day of gestation &group 3: Which consists of nine pregnant rats and were received prianil (lithium carbonate) 200mg/kg rat and caffeine 18mg/kg rat intragasteric durig the same period. The fetuses were obtained from mother were decapitated and the heads were fixed in buffered formaline for at least 3 hours. The specimens were collected, prepared and examined by routine haematoxylin &eosin and immunostained by (Ki-67) marker. Results: at 16, 18 and 21 days of gestation, the greatest mean value was recorded in group II, followed by group III, with the least value recorded in group I. Both group I and III revealed a decrease in area percent of (Ki-67) throughout the study, whereas in group II revealed an increase. Conclusions: The study offers a clear evidence that lithium during pregnancy causing cleft palate in fetus and caffeine could efficiently antagonize the teratogenicity of high doses of lithium on palate when both administrated.