The genetic heterogeneity of colon cancer suggests that it is actually more than one disease, and perhaps represents a conglomeration of genetically different diseases which happen to occur in the same organ. The progressively more refined genetic definition of colon cancer has uncovered and/or strengthened heretofore obscured associations with clinicopathologic features and risk factors and has led to the development of numerous useful clinical tests, some of which may also have therapeutic implications. It is certainly possible that we have only begun to "scratch the surface" of this heterogeneity. Other techniques--expression microarray, microRNAs, etc.--will likely add to this heterogeneity and suggest future diagnostic and therapeutic evaluations. In addition, recent data on APC gene mutations challenges the existing paradigm for colon cancer carcinogenesis and precursor lesions, which may in turn have clinical implications for cancer prevention.