The majority of atopic dermatitis (AD) patients respond satisfactorily to gentle bathing, frequent moisturizing, and topical medications. Second-line therapies for AD should be used in recalcitrant cases or in patients with uncontrolled disease despite compliance with first-line measures and avoidance of allergens. Recommended advanced therapies include phototherapy, especially narrowband ultraviolet B, systemic immunosuppressants, and a new biologic agent. Few studies have compared head-to-head efficacy of the different immunosuppressant therapies such as cyclosporine, methotrexate, azathioprine and mycophenolate mofetil. Therefore, the agent used is based on provider and patient preferences and can be decided on a case-by-case basis. Semin Cutan Med Surg 36:118-123 © 2017 Frontline Medical Communications. doi:10.12788/j.sder.2017.027Few studies have compared head-to-head efficacy of the different immunosuppressant therapies such as cyclosporine, methotrexate, azathioprine and mycophenolate mofetil.