Severe asthma presents significant management challenges. Patients can be difficult to control despite use of current standard-of-care therapy, including inhaled corticosteroids and long-acting β-agonists. Alternative diagnoses, noncompliance, and comorbidities all can influence asthma control, future risk, and response to currently available therapy. Definitions of severe asthma evaluate and address these confounding variables, and yet patients are still symptomatic despite aggressive, appropriate therapy. Severe asthma has a distinct pathophysiology including airway remodeling that contributes to the decreased effectiveness of standard therapy. Multiple phenotypes exist within severe asthma that likely require distinct therapeutic approaches to achieve control and improve long-term health outcomes. New therapeutic approaches to these distinct phenotypes will improve our understanding and treatment of this difficult-to-manage disease.