Research over the past decade has established that the progression from normal colonic epithelium to colon cancer is in every case a step-wise process in which specific pathologic and molecular markers can be identified for study and clinical therapy. Genetic and epigenetic instability appears fundamentally important to this process. We have now determined that this neoplastic progression occurs along a limited set of pathways, in which specific tumor suppressors are inactivated or oncogenes activated in a defined order. Although incomplete, our new understanding of the process of carcinogenesis in the colon has already significantly impacted patient care and will continue to do so for the foreseeable future. Increasingly rapid research developments and technologic advances will transform the way we prevent, diagnose, and treat this common and deadly form of cancer.