The discovery of two isoforms of the cyclooxygenase (COX) enzyme, COX-1 and COX-2, has provided the rationale for development of selective COX-2 inhibitors as a class of safer drugs for the treatment of pain, symptoms of osteoarthritis and rheumatoid arthritis (see reviews 1 ,2 ). Broadly speaking, COX-1 is the constitutive “house-keeping” enzyme responsible for production of prostaglandins (PG) involved in physiological functions such as gastrointestinal cytoprotection and platelet functions. In contrast, COX-2 is rapidly and strongly upregulated upon inflammatory stimuli. COX-2 is the predominant isoform responsible for production of PGs involved in pain, inflammation, and fever. Thus, the therapeutic actions of conventional nonsteroidal antiinflammatory drugs (NSAIDs), which inhibit both COX-1 and COX-2, can be attributed to their inhibition of PG production during inflammation. On the other hand, the dose-limiting gastrointestinal toxicity of NSAIDs can be explained by their inhibitory action on COX-1. It is hypothesized that a selective COX-2 inhibitor will achieve therapeutic efficacy in osteoarthritis, rheumatoid arthritis, and pain management while substantially improved gastrointestinal toxicity profile owing to its COX-2 selectivity. This hypothesis is now supported by an extensive amount of data from preclinical and clinical studies with approved COX-2 inhibitors, such as rofecoxib (3 ) and celecoxib (4 ), and COX-2 inhibitors currently in development, such as etoricoxib (5 ) and valdecoxib (6 ).