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Since 1990, molecular biologists have identified two distinct pathways, microsatellite instability (MSI) and chromosomal instability (CIN), which are involved in the pathogenesis of colon cancer (CC). Thus, a new paradigm has emerged with the discovery that CC is a heterogeneous disease; furthermore recent data have demonstrated that these two distinct pathways in colorectal carcinogenesis are characterized by a different clinical outcome. The implications for the clinicians are twofold; (1) tumors originating from the proximal colon have a better prognosis due to a high percentage of MSI\u2010positive lesions; and (2) location of the neoplasm in reference to the splenic flexure should be documented before group stratification in ongoing trials of adjuvant chemotherapy for CC. In the future, clinical decision\u2010making regarding adjuvant chemotherapy might be stratified according to the MSI status of cancers located proximally to the splenic flexure. J. Surg. 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