Asthma is a complex disease characterized by variable airflow limitation, hyperresponsiveness, and airways inflammation. Despite valuable therapeutic advances to control asthma symptoms in the last decade, a quantifiable proportion of patients with moderate to severe asthma continue to experience inadequate disease control, highlighting an important unmet need. In animal models of asthma, interleukin (IL)-9 regulates the development of airway inflammation, mucus production, airway hyperresponsiveness, and airway fibrosis largely by increasing mast cell numbers and activity in the airways. Mast cells are involved in the pathogenesis of eosinophilic and noneosinophilic asthma. Thus, targeting the IL-9 pathway may provide a new therapeutic modality for asthma. The purpose of this review is to summarize the IL-9-mast cell axis in the pathogenesis of asthma and discuss clinical studies with a humanized anti-IL-9 monoclonal antibody, MEDI-528, in subjects with asthma.