Asthma is characterized by abnormal immune cell accumulation and activation in the airways as well as dysfunction of specialized parenchymal cells. Research strategies to define asthma pathogenesis have focused on the hypothesis that this altered state is a consequence of an excessive allergen-driven response. Drug development for asthma has been directed at improving existing agents and expanding new modalities that target the Th2 allergic cascade. Significant opportunities are being pursued in each of these areas. However, this strategy may not account for some critical aspects of asthma pathogenesis. Alternative considerations include the need for a multidisciplinary approach to dissect the complexity of the asthma phenotype as well as a better understanding of nonallergic factors (especially viral reprogramming of airway behavior) in the development of the phenotype. Each of these considerations may provide an alternative strategy for further drug development for asthma and other complex diseases.