This review of the molecular and cellular changes in the different pathways of colorectal carcinogenesis sets out the classic adenoma-carcinoma sequence of the large bowel as a stepwise series of pathologic neoplastic changes associated with accumulation of genetic and epigenetic molecular alterations. The 2 major types of genomic instability found in colorectal cancers are chromosomal instability (CIN) and microsatellite instability (MSI). CIN is often associated with mutated APC. MSI is due to defective DNA mismatch repair. The associated familial cancer susceptibility syndromes are familial adenomatous polyposis coli, due to inherited APC mutations, and Lynch Syndrome or hereditary nonpolyposis colorectal cancer syndrome, due to inherited mutations in one of the mismatch repair genes (predominantly MLH1 and MSH2). In the CpG island methylator phenotype, a number of genes become transcriptionally silenced because of hypermethylation of their promoters, and this represents a key epigenetic mechanism of inactivation of tumor suppressor genes, including certain DNA repair genes. An overview of the contributions of CIN, MSI, and CpG island methylator phenotype to the different pathways of colorectal carcinogenesis allows categorization of colorectal cancers into 5 major groups on the basis of their molecular and pathologic characteristics.