Several recent advances have been made in our understanding of the pathogenesis of endometrial tumours, particularly endometrioid endometrial carcinoma (EEC). Mutations in the PTEN gene and microsatellite instability (MSI) are common genetic abnormalities in EECs, and distinguish these lesions from other histological subtypes of endometrial carcinoma. Endometrial precancers are monoclonal lesions that share a common genetic lineage with invasive EEC, including PTEN mutations and MSI. Mutations of the PTEN tumour suppressor gene have been identified in histologically normal-appearing endometrium exposed to oestrogen, 18-55% of endometrial precancers and 26-80% of EECs. PTEN has been shown to play several roles in tumour suppression, including cell cycle arrest and promotion of apoptosis. Loss of PTEN function predisposes endometrial cells to neoplastic transformation, particularly in high-oestrogenic states. MSI is another common alteration seen in EECs and endometrial precancers, and some studies have reported an association between MSI and PTEN mutations. The replication error that results in MSI may facilitate the development of PTEN mutations in some, but not all, cases of EEC. The prognostic significance of PTEN gene mutations and MSI in endometrial carcinoma is controversial. Further study is needed to delineate the different pathogenetic pathways of EEC and their natural history.