Atopic dermatitis (AD) is a pruritic, relapsing skin disorder that negatively impacts the quality of life of those affected and that of their families. Treatment options for AD encompass a variety of emollients, topical corticosteroids, topical immunomodulators, phototherapy, and systemic agents. Such agents as systemic corticosteroids, cyclosporine, azathioprine, interferon-gamma, methotrexate, and mycophenolate mofetil have been shown to be efficacious in the treatment of moderate-to-severe AD but are not officially approved for this purpose. In this article, we review some of the data supporting efficacy of these medications and discuss some of the adverse events associated with their use.