Introduction p38R is a member of the well characterized mitogen activated protein (MAPa) kinase family of serine/threonine protein kinases. p38R is widely expressed in endothelial, immune, and inflammatory cells and plays a central role in the regulation of proinflammatory cytokine production including TNF-R, IL-1β, and IL-6. 1, 2 Selective blockade of any one of these cytokines with biologic agents has proven efficacious for inflammatory diseases including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. 3, 4 The p38 subfamily of MAP kinases includes four isoforms (p38R, p38β, p38γ, and p38δ) that are encoded by separate genes. Analysis of differential tissue expression and activation of these isoforms in synovial tissue extracted from RA patients has suggested that the p38R isoform is overactivated within inflamed tissue and may be a preferred target for intervention in the disease. 5-7 This expectation has prompted a huge investment by the pharmaceutical industry in the development of p38R inhibitors as potential oral disease modifying antirheumatic drugs (DMARDs). 8, 9 This Perspective will summarize key learnings from over 15 years of industrial experience with p38R as a drug target, with a focus on the rational design of highly selective small molecule inhibitors, followed by a discussion of data for examples 1-11 that have entered into or are recruiting for phase 2 clinical studies (summarized in Table 1). To date, these results have been disappointing. We conclude that p38R inhibition alone is unlikely to be a successful strategy toward treating chronic inflammatory disorders. Others have also concluded that “the era of optimism surrounding the use of p38 MAPK inhibition for the treatment of RA is over”. 10