Distinction between endometrioid and serous carcinomas of the endometrium has important prognostic and therapeutic implications. Misdiagnosing a serous carcinoma as endometrioid can have significant consequences for the patient and pathologist. Although many cases are straightforward and easy to classify, there are occasional problematic cases. This review focuses on strategies that help differentiate between low-grade endometrioid carcinoma and serous carcinoma of the endometrium. We will discuss clinical, morphologic, and immunohistochemical differences between the 2 entities and provide practical tips for practicing pathologists when confronted with this differential diagnosis.