Chemoprevention represents a highly promising approach for the control of cancer. That nonsteroidal anti-inflammatory drugs (NSAIDs) prevent colon and other cancers has led to novel approaches to cancer prevention. The known inhibitory effect of NSAIDs on the eicosanoid pathway prompted mechanistic and drug development work focusing on cyclooxygenase (COX), culminating in clinical trials of cyclooxygenase 2 (COX-2) inhibitors for cancer prevention or treatment. However, two COX-2 inhibitors have been withdrawn due to side effects. Here we review several pathways of the eicosanoid cascade that are relevant to cancer; summarize the evidence regarding the role of COX-2 as a target for cancer prevention; and discuss several of the molecular targets that may mediate the chemopreventive effect of NSAIDs. The clinically modest results obtained to date with COX-2 specific inhibitors used in cancer prevention; the multiple COX-2-independent targets of both NSAIDs and COX-2 inhibitors; and the limitations of some COX-2 inhibitors indicate that exploiting these (non-COX-2) molecular targets will likely yield effective new approaches for cancer chemoprevention.