The chemopreventive efficacy of NSAIDs against colorectal cancer has been established. Also, NSAIDs may decrease the incidence of carcinomas of the esophagus, stomach, breast, lung, prostate, urinary bladder and ovary. The clinical use of these agents is limited to patients with familial adenomatous polyposis (FAP), which may benefit from chemopreventive treatment with sulindac or the selective COX-2 inhibitor celecoxib. The mechanism of chemoprevention by NSDAIDs is still a matter of debate. COX-2 inhibition explains at least part of the observed effects, however, other targets have been proposed. The effect of NSAIDs is incomplete and molecular mechanisms related to resistance need to be studied. Also, more effective chemopreventive regimens are needed; combination therapy appears attractive, potentially increasing efficacy and decreasing toxicity. This review discusses molecular and clinical aspects of chemoprevention of the adenomacarcinoma sequence with NSAIDs or COX-2 inhibitors.