The development of colorectal neoplasms can be characterized by an ordered series of events that are referred to as the dysplasia-carcinoma sequence. These histologic changes occur as a result of genetic alterations in proto-oncogenes and tumor-suppressor genes. This review emphasizes important studies characterizing the role of four genes, APC, Cox-2, DCC/Smad4, and the mismatch repair genes, in colorectal carcinogenesis.