Azathioprine, cyclophosphamide, methotrexate, cyclosporine, and MMF are the nonsteroidal immunosuppressive agents most commonly used by dermatologists. Azathioprine has a relatively good safety profile and is therefore often preferred for the treatment of chronic eczematous dermatitides and bullous disorders. Awareness of the role of genetic polymorphisms in its metabolism can increase the efficacy and safety of this drug. Cyclophosphamide is an antimetabolite that has a more rapid onset of immunosuppressive effect than azathioprine but has significant short- and long-term toxicity. It is of use in fulminant, life-threatening cutaneous disease. Methotrexate is an antimetabolite that has significant anti-inflammatory activity. Despite its hepatotoxicity, its role in inflammatory dermatoses is broadening. Cyclosporine has potent T-cell inhibitory effects secondary to interference with intracellular signal transduction, and its use in dermatology is rapidly expanding. Given the evidence for cumulative renal toxicity, it currently has a role in the short-term treatment of refractory psoriasis and atopic dermatitis, and in select inflammatory dermatoses. MMF is an immune suppressant with wide potential dermatologic applications, especially for bullous disorders, pyoderma gangrenosum, and psoriasis. It has a mechanism of action similar to azathioprine, and it is generally well tolerated. Although some studies found a slightly higher incidence of lymphoproliferative malignancies, MMF has a better overall safety profile than azathioprine. It is more expensive, however. Both mycophenolate and azathioprine should be used in conjunction with oral corticosteroids because they are "steroid sparing" but not "steroid replacing." They are usually required when it is impossible to reduce steroids to an acceptably low level. When they are added, as they become effective, the corticosteroid taper is resumed toward the target maintenance dose. Alefacept, efalizumab, etanercept, and infliximab are the immunobiologic agents currently most commonly used by dermatologists. Alefacept, the first immunobiologic agent to be approved for the treatment of adult patients with moderate to severe plaque-type psoriasis, is a fusion protein that blocks T-cell activation and selectively reduces memory T cells. Because of its unique mechanism of action, alefacept is considered to be the only remittive biologic agent. Therefore, patients who respond effectively to alefacept can enjoy long-lasting therapy-free reprieves for more than 7 months. Alefacept is also safe; safety and tolerability profiles were shown to be similar to placebo in phase 3 clinical trials. Similar to all of the immunobiologic agents, data on the potential for the development of malignancies require longer follow-up periods before a possible role of these agents in the development of malignancy can be excluded. The intramuscular route of administration, and the need for weekly CD4+ T-cell counts, also distinguishes alefacept, because it requires the patient to make weekly visits to a physician's office. Efalizumab, a humanized monoclonal antibody directed against CD11a, is indicated for the treatment of chronic moderate to severe plaque-type psoriasis. Unlike alefacept, efalizumab is administered as a weekly SC injection. Thrombocytopenia was reported in a small percentage of clinical trial patients; therefore, platelet counts must be monitored throughout treatment. Efalizumab is generally well tolerated but, similar to many of the systemic immunomodulators previously discussed, on cessation of therapy, some patients have experienced clinically significant relapse or exacerbation of psoriasis. Although long-term safety data have not been established for any of the immunobiologic agents, efalizumab has been shown to have a favorable side-effect profile and potential as a long-term therapeutic agent for chronic psoriasis. Etanercept is a dimeric fusion protein that inhibits TNF-α. Etanercept is FDA-approved for the treatment of psoriasis, psoriatic arthritis, and RA, and for reducing signs and symptoms of moderate to severe active polyarticular-course juvenile RA. Etanercept has a favorable safety profile. It is the only immunobiologic agent of the four discussed that does not require laboratory monitoring. Infliximab is a chimeric monoclonal antibody that targets TNF-α. It is currently indicated for the treatment of RA and Crohn's disease but has shown efficacy for a wide array of dermatologic conditions, especially psoriasis and psoriatic arthritis, pyoderma gangrenosum, and the cutaneous manifestations of Behçet's syndrome. High percentages of patients with psoriasis respond to infliximab, and response rates tend to be rapid and long-lasting. Infliximab has several potential drawbacks, however, including its route of administration, which is by means of an IV drip over the course of several hours. Infusion reactions also have been a concern, although less than 1% of infusion reactions in clinical trials were considered serious. Other issues have been postmarketing reports of worsening heart failure, reactivation TB, and other opportunistic infections. In addition, some patients have developed neutralizing antibodies. Unlike methotrexate and cyclosporine, for example, infliximab is neither hepatotoxic nor nephrotoxic; it therefore represents a useful therapeutic agent for patients with severe psoriasis who have contraindications to other immunosuppressive agents or who are recalcitrant to other therapies.