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Although many atopic dermatitis patients can be treated satisfactorily with topical medications and systemic anti-itch approaches, a smaller subset require more aggressive systemic therapies. Familiarity with the latest literature on the benefits and risks of these treatments will enable the clinician and patient to select the most appropriate therapy based on the patient's lifestyle, assessments of risks and comorbidities.Additional data have come to light altering the risk and benefit ratio of certain systemic atopic dermatitis therapies. In 2011, we saw several head-to-head, randomized controlled trials of established systemic medications for the treatment of atopic dermatitis. A few new systemic atopic dermatitis treatments have highlighted how targeted therapies may inform us about disease pathogenesis.In light of the risk of hepatosplenic T-cell lymphomas, a greater degree of caution is warranted in the use of azathioprine. NBUVB, mycophenolate, and methotrexate remain the reasonable first-line systemic treatment options for atopic dermatitis. A brief run-in with high-dose cyclosporine to clear atopic dermatitis followed by maintenance with low-dose cyclosporine or cellcept – both of which have better risk and benefit ratios is a reasonable approach. Interferon gamma and intravenous immunoglobulin, although expensive, are potential options, and possibly most ideal for atopic dermatitis patients plagued by significant viral skin infections such as eczema herpeticum. A better understanding of the immunopathogenesis of atopic dermatitis will come with the exploration of novel targeted therapies.