Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used prescription and nonprescription drugs in the world. The discovery of cyclooxygenase (COX) as the target of NSAIDs, the subsequent identification of two isoforms of COX (COX-1 and COX-2), and studies of their regulation and sites of expression led to the hypothesis that COX-2 is the molecular target for the anti-inflammatory and analgesic effects of NSAIDs. A corollary was that COX-2-selective inhibitors (COXIBs) would retain the desirable effects of NSAIDs without some of their liabilities (e.g., gastrointestinal toxicity, which was ascribed to COX-1 inhibition). The first marketed COXIBs exhibited reduced gastrointestinal side effects relative to traditional NSAIDs and were enormous commercial successes. However, clinical trials testing the hypothesis that COXIBs prevent recurrence of premalignant colon polyps uncovered adverse cardiovascular effects that are mechanism based. This review provides an overview of the discovery, development, and difficulties of the COXIBs, a perspective on what has been learned, and speculation on the way forward.