The correct diagnosis of asthma is usually easily made and most patients with asthma respond to therapy. Approximately 5% of patients with asthma, however, have disease that is difficult to control despite taking maximal doses of inhaled medications. Patients with therapy-resistant or difficult-to-control asthma require a rigorous and systematic approach to their diagnosis and treatment. The first step is evaluation and testing directed at determining that asthma is the correct diagnosis. Many diseases mimic asthma and these alternate diagnoses should be considered. The second step is to identify and eliminate triggers that worsen asthma. Cigarette smoking, occupational exposures, and allergic rhinitis contribute to worsening disease. Most patients with "difficult asthma" require treatment with high-dose inhaled corticosteroids and long-acting inhaled beta(2)-agonists. Despite maximal inhaled therapy, these patients will require either frequent bursts or chronic daily therapy with oral corticosteroids. These patients may have "resistant" inflammation with a persistent inflammatory state. Numerous studies also suggest that compliance with asthma therapy is poor. Combination therapy with inhaled corticosteroids and long-acting beta(2)-agonist in a single inhaler may improve patient compliance. In selected patients, additional therapy with leukotriene modifiers or anti-IgE antibody can result in improved asthma control and may allow tapering of corticosteroids. Use of methotrexate is not justified based on current data. Emerging evidence suggests that different phenotypes of difficult or therapy-resistant asthma exist. Recognition of these subgroups allows tailored therapy and prevents overmedication in an attempt to normalize lung function in patients with irreversible airflow obstruction.