DNA-binding protein SATB2, also known as Special AT-rich sequence-binding protein 2, is a nuclear matrix-associated transcription factor. SATB2 acts as a docking site for chromatin remodeling enzymes and recruits co-activators and co-repressors to control nuclear gene expression. SATB2 also regulates skeletal development, osteoblast differentiation, and modulates immunoglobulin expression. In normal tissues, strong nuclear SATB2 expression is observed in essentially all glandular cells lining the lower gastrointestinal tract, including the appendix, colon, and rectum. SATB2 is also expressed in a subset of neuronal cells from the cerebral cortex and hippocampus. In tumor tissues, SATB2 is detected in cancer cells of colorectal origin and may function as a clinically useful diagnostic marker for colorectal cancer (CRC). In a multi-cohort study with 1882 primary and metastatic CRCs, SATB2 shows high sensitivity (85%) for CRC, which is further enhanced to 93% when stained in conjunction with Cytokeratin 20. A recent study showed SATB2 expression in 89% of medullary carcinomas of the large intestine. SATB2 has been suggested as a valuable prognostic marker: high SATB2 expression was determined as an independent marker of good prognosis and sensitivity to chemotherapy and radiation in CRC while loss of SATB2 expression was correlated with poor prognosis in laryngeal carcinoma patients.