Colorectal cancer is a leading cause of death by cancer in the western world. Present oncological treatments have relatively little impact on long term survival and hope is pinned on screening. Current population-based screening methods are insufficient in reducing colorectal cancer deaths, therefore new approaches are needed. One approach is chemoprevention, which targets specific signalling pathways to interfere in the process of carcinogenesis. However, it is of great importance to critically assess the benefits of chemoprevention in comparison to its risk and inconvenience. It is unlikely that chemoprevention can be used in a wide unselected population, but is more favourable in high risk groups such as individuals especially susceptible to neoplasia because of environmental risk factors, patients with inflammatory bowel disease, those with a hereditary predisposition to CRC (FAP, Lynch, HNPCC) and patients with a previous history of colorectal cancer or adenomatous polyps. CRC is not one disease but a heterogeneous group of diseases with different underlying molecular mechanisms. Both prevention and therapy needs to be tailored to the molecular subtype of the cancer in question. This review summarises the evidence for the chemopreventive efficacy of the major agents investigated to date and their proposed molecular mechanism(s) of action.