p38 mitogen activated protein (MAP) kinase remains the most compelling therapeutic target for oral drug intervention for a wide range of autoimmune disorders based on the central role this enzyme plays in inflammatory cell signaling. Efforts to discover inhibitors of p38 suitable for clinical investigation have continued to escalate in part due to the incredible diversity of unique chemotypes reported to inhibit the enzyme. Since 1993, at least seventeen p38 inhibitors have been reported to have entered into clinical trials. Next generation inhibitors have been disclosed with improved potency for p38 and enhanced selectivity versus other protein kinases. Over the last three years, there have been multiple reports of cytokine suppression in humans following oral administration of p38 inhibitors. These results, in addition to proof of concept studies in rheumatoid patients, have established p38 inhibition as an avenue for the future management of pro-inflammatory cytokine based diseases. This review describes the discovery at Roche of novel p38 inhibitors which have advanced into clinical trials. The pharmacology of the Roche compounds is then compared with eight chemically distinct p38 inhibitors known to have entered clinical development.