 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 osteo arthritis. The development of selective cox, 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 cox, one in cox, two inhibition, major chemical classes of selective cox, two inhibitors, and recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NONSAIDs, dual cox slash LOX inhibitors, and anti-TNF therapy. Despite tremendous progress in the last decade, designing a safe, effective, and economical therapy for treating inflammatory conditions remains a major challenge. This article was authored by Praveen Rao and Edward E. Naus.