Severe atopic dermatitis has a profound effect on many aspects of the patient's life, and a combination of topical and systemic treatment is often necessary to control the disease. Systemic corticosteroids are rapidly effective, but should only be used short term for severe exacerbations because of their many long-term side effects. In chronic cases, starting another systemic immunosuppressant therapy while tapering off corticosteroids should be considered. The usefulness of cyclosporin A, azathioprine, and methotrexate has been documented in clinical trials. Cyclosporin A is rapidly effective, but has a narrow therapeutic index and possible renal toxicity. Azathioprine and methotrexate have a slower onset of action and are good treatment options for many patients, but are not always tolerated. Mycophenolate mofetil, mycophenolate sodium and biologicals are other alternatives, but need to be assessed in larger randomized trials. Despite the available therapeutic repertoire, there remain patients with very severe disease in whom we are unable to obtain satisfactory control. The therapy for patients with severe psoriasis has been revolutionized during the last decade, due to the development of targeted biological therapy, and it is indeed the hope that a similar process is about to emerge also for patients suffering from severe atopic dermatitis.