Non-steroidal anti-inflammatory drugs are chemopreventive agents in colorectal cancer. Non-steroidal anti-inflammatory drugs do not, however, offer complete protection against adenoma and carcinoma development. There is increasing interest in combining non-steroidal anti-inflammatory drugs with agents that target specific cell signalling pathways in malignant and premalignant cells. This review aims to describe the current knowledge regarding the efficacy of peroxisome proliferator-activated receptor-gamma ligands, cholesterol synthesis inhibitors (statins), epidermal growth factor signalling inhibitors and tumour necrosis factor-related apoptosis-inducing ligand against colorectal neoplasms and the rationale for combining these drugs with non-steroidal anti-inflammatory drugs to improve efficacy in the chemoprevention of colorectal cancer, a PUBMED computer search of the English language literature was conducted to identify relevant papers published before July 2004. Peroxisome proliferator-activated receptor-gamma ligands and statins, both in clinical use, reduce the growth rate of human colon cancer cells in vitro and in rodents models. In vitro, preclinical in vivo and clinical studies have shown efficacy of epidermal growth factor signalling inhibition in colorectal cancer. In vitro, tumour necrosis factor-related apoptosis-inducing ligand induces apoptosis in human colon cancer cells, but not in normal cells. These drugs have all been shown to interact with non-steroidal anti-inflammatory drugs in colorectal cancer cells and/or in rodent models. Combinational regimen are a promising strategy for the chemoprevention of colorectal cancer and should be further explored.