SATB2 is part of the family of matrix attachment region-binding transcription factors, and has developmental roles in craniofacial, neural, and osteoblastic differentiation. Recently, SATB2 has been shown to be highly expressed in the epithelium of the lower gastrointestinal tract, with a relatively narrow expression profile in malignancies, including colorectal/appendiceal adenocarcinomas, tumors of osteoblastic differentiation, and renal/urothelial carcinomas. SATB2 has gained interest as a relatively specific marker of colorectal differentiation, with potential applications including determining origin of adenocarcinomas of unknown primary and distinguishing primary ovarian mucinous adenocarcinomas from colorectal metastases. Here, we briefly review the biology, expression profile, and potential histologic applications of SATB2.