Although up to 70-80% of colon cancers are believed to be preventable, colorectal cancer is the second most common cause of cancer deaths in the industrialised world and trends towards increasing obesity suggest the potential for a further significant increase in its worldwide incidence. There is therefore an urgent need to develop novel methods for the prevention and treatment of this cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) are chemopreventive against colorectal cancer, mostly through their inhibitory effects on the cyclooxygenase isoform COX-2. COX enzymes represent the committed step in prostaglandin biosynthesis and it is predominantly increased COX-2-mediated prostaglandin-E2 (PGE2) production that has a strong association with colorectal neoplasia, by promoting cell growth, cell survival, migration, invasion and angiogenesis. COX-2 is overexpressed in the majority of colon cancers and a subset of adenomas. COX-1 and COX-2 inhibition by traditional NSAIDs, such as aspirin, although chemopreventive have some side effects. Interestingly, the use of COX-2 selective NSAIDs has also shown promise in the prevention/treatment of colorectal cancer while having a reduced impact on the gastric mucosa. However, the prolonged use of high dose COX-2 selective inhibitors is associated with a risk of cardiovascular side effects. There is therefore an urgent need to further our understanding of the downstream mechanisms by which PGE2 promotes tumorigenesis and hence identify safer, more effective strategies for the prevention of colorectal cancer. In particular, PGE2 synthases and E-prostanoid receptors (EP1-4) have recently attracted considerable interest in this area. Recent evidence suggests that the EP4 receptor may represent an important target for the prevention/treatment of colorectal cancer. It is hoped that the inhibition of the synthesis and signalling of those prostaglandins most highly associated with colorectal tumorigenesis, such as PGE2, may have advantages over COX-2 selective inhibition and therefore represent more suitable targets for long-term chemoprevention. Since COX-2 is found to be overexpressed in cancers such as breast, gastic, lung, and pancreatic, these approaches may have broad implications for the prevention/treatment of other malignancies.