Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide. Although conclusive evidence is still lacking, epidemiologic studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has chemopreventive properties against CRC. Similarly, regular consumption of mesalazine, a drug structurally related to NSAIDs, seems to reduce the risk of CRC in patients with ulcerative colitis. These observations are supported by a large body of experimental data showing the ability of such drugs to inhibit multiple pathways that sustain colon carcinogenesis. This review summarizes the current information on the molecular mechanisms by which NSAIDs and mesalazine could interfere with CRC cell growth and survival.