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One of the most promising approaches for minimizing the side effects of nonsteroidal antiinflammatory drugs (NSAIDs) is to concurrently inhibit the activities of both 5-lipoxygenase (5-LO) and cyclooxygenase (CO). Many such dual inhibitors of prostaglandin (PG) and leukotriene (LT) production in vitro have been described but, despite intense pharmaceutical research efforts, the translation of this in vitro activity into in vivo efficacy has proven difficult. Chemical modification of one series of inhibitors, the 2,6-di-tert­ butylphenols, has provided a variety of dual inhibitors with antiinflammatory efficacy and superior gastrointestinal (GI) safety. Whereas optimization of the di-t-butylphenols for in vitro activity, inhibitory specificity, oral availability and antiinflammatory efficacy resulted in the identification of Cl-1004 and other clincal candidates, optimization of other chemical series typically resulted in dual inhibitors with potent in vitro effects but little in vivo activity. The development of several dual inhibitors, including tepoxalin, tebufelone and CI-986, has been limited by drug metabolism issues. Translation of the attractive preclinical antiinflammatory and safety profile of dual inhibitors to the clinical arena awaits the completion of thorough clinical studies, such as those currently underway with CI-1004.