 This review traces the history and mechanism of action of nonsteroidal anti-inflammatory drugs, NSAIDs, which have been used to treat inflammatory conditions such as rheumatoid arthritis and osteoarthritis. The development of selective cocks, two inhibitors, their adverse cardiovascular effects, and recent discoveries targeting the design of effective anti-inflammatory agents with reduced side effects are also discussed. The review covers the structural basis for cocks, one in cocks, two inhibition, methods used to evaluate cocks, one slash cocks, two inhibition, and major chemical classes of selective cocks, two inhibitors. Recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor and NSAIDs, dual cocks slash LOX inhibitors, and anti-TNF therapy are also discussed. Despite tremendous progress in the last decade, designing a safe, effective, and economical therapy for treating inflammatory conditions remains a major challenge.