About 10% of endometrial cancers are initiated by a mutation (most frequently P286R) in polymerase epsilon (encoded by the POLE gene). Polymerase epsilon is a “housekeeping” DNA polymerase responsible for the bulk of DNA replication during normal cell divisions. These mutations render POLE highly-error prone. POLE endometrial cancers have paradoxical properties; for example, they have the highest mutation rates ever described in human cancers, yet have a fairly good prognosis. We have recapitulated the P286R mutation through conditional genetic approaches and are using these models to study this common but poorly understood subtype of human endometrial cancer. Please see JCI 2018 128(9):4179.