Eicosanoids play an important role in numerous physiologic and pathophysiologic processes in the gastrointestinal tract, including maintenance of mucosal integrity, stimulation of mucus and electrolyte secretion, and inflammation. A rapidly growing body of evidence implicates COX-2 in colorectal carcinogenesis. COX-2 has been shown to alter cellular adhesion, apoptosis, and angiogenesis, contributing to its neoplastic potential. NSAIDs appear to attenuate this potential by mechanisms that are COX-2 dependent and independent. Several advances have been made in understanding the details of COX-2 regulation. The downstream effect of COX-2-dependent metabolites varies with the enzymatic machinery present in a particular cell, the level of COX activity, differences in location and types of prostaglandin receptors, and differences in signal transduction pathways. Further studies are needed to understand better these complex interactions, which may provide insight into the role of COX-2 in pathologic conditions, such as intestinal inflammation and colorectal cancer.