Asthma is a common chronic condition among children that is associated with significant morbidity. Because medication non-adherence is an important cause of excess morbidity, the National Asthma Education and Prevention Program guidelines have called for the development of more effective adherence programs. Schools represent a logical setting where adherence programs could reach the inner-city, low-income, and ethnically diverse populations that have the highest morbidity and lowest adherence. A recent clinical trial demonstrated that supervised therapy of daily controller medication at school increased medication adherence and asthma control among primarily African-American students in urban, low-income elementary schools. This study aims to evaluate: (1) the effectiveness of supervised therapy when administered by the community under real world conditions via a randomized controlled trial of 500 children with asthma in a large urban, predominantly Hispanic school system; (2) the cost-effectiveness of supervised therapy from the societal perspective using dollars per quality-adjusted life year (QALY) gained; and 3) the program’s implementation fidelity, optimal delivery mechanisms, and construct validity via a comprehensive process evaluation. Supervised therapy is hypothesized to be both an effective and cost-effective mechanism to improve population-level asthma control among students with asthma. This project will provide critical information regarding the program’s value, feasibility, and sustainability within communities with large asthma burden. In addition, it will provide important recommendations to accelerate the adoption of guideline-based care for students with asthma in urban, low-income, and ethnically diverse populations. With this information, policy makers can optimize the use of scarce public health resources by adopting programs that efficiently maximize child health.