Glucocorticosteroids are the backbone of asthma therapy and are administered mainly by the inhaled route. Patients with "difficult" asthma are not a single homogeneous group. Some are stable on high-dose steroid therapy but experience unacceptable side effects; others remain unstable despite receiving high doses of inhaled or oral steroids. Several different steroid-sparing and alternative agents have been tried, with varying degrees of success. Some success has been achieved with conventional immunosuppressants such as methotrexate, gold, and cyclosporin A, but these agents can be justified only in a limited range of cases. Leukotriene receptor antagonists have proved a useful addition to asthma therapy and have been shown to have a modest steroid-sparing effect. Although the existing range of alternative agents has not proved to be particularly effective, several new therapeutic agents have been developed to target specific components of the inflammatory process in asthma. These include IgE antibodies, cytokines, chemokines, and vascular adhesion molecules. Future developments might include better forms of immunotherapy and strategies targeting the remodeling of structural elements of the airways.