Increasing evidence indicates that Non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), can reduce the number and size of adenomas in patients with familial adenomatous polyposis as well as the incidence of colorectal cancer. The COX enzyme family consists of the classic COX-1 and a second enzyme, COX-2, which is induced by various stimuli, such as mitogens and cytokines. While it is well proven that COX-2 overexpression is a central event in colorectal carcinogenesis, that prostaglandins (PGs) can contribute to tumorigenesis, and that COX-2 selective inhibitors are active chemopreventive agents, the molecular mechanisms by which NSAIDs exert their chemopreventive effect is not fully understood. However, significant advances have been made in understanding the interference of NSAIDs with the pathways that control cell growth and survival even independently from their COX-inhibiting properties, making their use attractive both alone and in combination with standard therapies in the treatment of advanced colorectal cancer. In addition, the recently recognized anti-angiogenic and radiosensitizer properties of COX-2 inhibitors support, further suggest their use in the adjuvant setting.