Endometrial cancer is the most common malignant tumor of the female genital tract in the developed world. Increasing evidence suggests that the majority of cases can be divided into two different types ofendometrial cancer based on clinico-pathological and molecular characteristics. Type I is associated with an endocrine milieu of estrogen predominance. These tumors are ofendometroid histology and develop from endometrial hyperplasia. They have good prognosis and are sensitive to endocrine treatment. Type II endometrial cancers are not associated with a history of unopposed estrogens and develop from the atrophic endometrium of elderly women. Mainly, they are of serous papillary or clear cell morphology, have a poor prognosis and do not react to endocrine treatment. Both types of endometrial cancer probably differ markedly with regard to the molecular mechanisms of transformation. The transition from normal endometrium to a malignant tumor is thought to involve a stepwise accumulation of alterations in cellular mechanisms leading to dysfunctional cell growth. This chapter reviews the current knowledge of the molecular mechanisms commonly associated with development of type I and type II endometrial cancer.