Colorectal cancer (CRC) remains a common and often lethal disease. The classic adenoma-carcinoma sequence was defined on histologic grounds but over the last 25 years, the molecular basis of this process has been progressively clarified. There are at least three distinct molecular pathways to CRC: the chromosomal instability (CIN) pathway is thought to be largely driven by mutational events in oncogenes and tumor suppressor genes, the microsatellite instability pathway is responsible for Lynch syndrome CRCs and is driven by mutations in one of the DNA mismatch repair genes, and the epigenetic pathway is thought to be driven in large part by hypermethylation-induced silencing of tumor suppressor-like genes. The molecular understanding of this sequence has had a profound impact on our understanding of the process(s) of colonic carcinogenesis and this understanding has begun to change the clinical care of patients with colonic polyps and cancer including changes in therapy of established CRCs (anti-epidermal growth factor receptor antibody therapy is no longer offered to patients with mutant KRAS CRCs), identification of high-risk groups (diagnosis of Lynch syndrome by molecular analysis of CRCs) and the management of precursor lesions (identification of the serrated polyp pathway to CRC).