Evaluation of the endometrial biopsy is a challenge to practicing pathologists, largely due to the wide range of morphologic patterns resulting from both normal and abnormal cyclic changes, exogenous hormones, infections, and intrauterine tumors. Successfully addressing these challenges requires that the practitioner (i) understand the clinical questions being asked, (ii) have a realistic expectation for answering these questions, and (iii) have a systematic approach to resolving these questions in the context of these expectations. The approach outlined begins with the subdividing of women with endometrial alterations into three general categories: (i) women in their fourth decade undergoing evaluation for infertility, (ii) women in their fifth decade who experience abnormal uterine bleeding, and (iii) women in their sixth decade and beyond who experience postmenopausal bleeding. The clinical expectations for each group are unique, as are the morphologic patterns most commonly encountered. Algorithms for the laboratory management of cyclic changes, dysfunctional bleeding, and mixed-pattern endometria are provided, as are pitfalls in interpretation and exclusion of neoplasia.