Over the past 20 years exciting developments in clinical and basic research have opened up the possibility of NSAID-induced colorectal cancer chemoprevention. In particular, disclosure of the multistep genetic pathway of colorectal carcinogenesis and recognition of the impact of the COX-2 gene on this process have been of utmost importance. These findings have led to the possibility of colorectal cancer prevention by the administration of agents such as NSAIDs. Although it is accepted that these agents are potent inhibitors of colorectal carcinogenesis, their side effects in long-term use are of concern to clinicians dealing with colorectal cancer prevention. Moreover, neither the dose nor the duration of the medication, nor the most ideal compound with respect to protective effects against colorectal cancer, has been defined. Recently, selective COX-2 inhibitors have been developed which may show additional benefit compared to the classical NSAIDs. However, their efficacy and safety profiles need to be established firmly before large-scale use in colorectal cancer prevention can be considered. Based on the exciting developments it is anticipated that a more precise understanding of the molecular details of colorectal carcinogenesis will finally lead to the optimal chemopreventive regimen.