Because of an increasing prevalence, morbidity, and mortality associated with asthma, the National Heart, Lung, and Blood Institute created the Asthma Clinical Research Network and the Childhood Asthma Research and Education Network to improve public health. The objectives of these clinical research networks are to conduct multiple, well-designed clinical trials for rapid evaluation of new and existing therapeutic approaches to asthma and to disseminate laboratory and clinical findings to the health care community. These trials comprise a large proportion of the data driving the treatment guidelines established and reviewed by the National Asthma Education and Prevention Program. This article will review the basic design and major findings of selected Asthma Clinical Research Network and Childhood Asthma Research and Education Network trials involving both adults and children with asthma. Collectively, these studies have helped refine the therapeutic role of existing controller medications, establish standard models for side-effect evaluation and risk-benefit models, validate symptom-based assessments for asthma control, and identify baseline characteristics that might predict individual patient responses. Remaining challenges include shaping the role of novel therapeutics in future guidelines, incorporating pharmacogenomic data in treatment decisions, and establishing better implementation strategies for translation to community settings, all with the goal of reducing the asthma burden on society.