Abstract Background Asthma is a common complex disease responsible for considerable morbidity and mortality, particularly in urban minority populations. The Mechanistic Indicators of Childhood Asthma study was designed to pilot an integrative approach in children's health research. The study incorporates exposure metrics, internal dose measures, and clinical indicators to decipher the biological complexity inherent in diseases such as asthma and cardiovascular disease with etiology related to gene-environment interactions. Methods/Design 205 non-asthmatic and asthmatic children, (9-12 years of age) from Detroit, Michigan were recruited. The study includes environmental measures (indoor and outdoor air, vacuum dust), biomarkers of exposure (cotinine, metals, total and allergen specific Immunoglobulin E, polycyclic aromatic hydrocarbons, volatile organic carbon metabolites) and clinical indicators of health outcome (immunological, cardiovascular and respiratory). In addition, blood gene expression and candidate SNP analyses were conducted. Discussion Based on an integrative design, the MICA study provides an opportunity to evaluate complex relationships between environmental factors, physiological biomarkers, genetic susceptibility and health outcomes. Project approval IRB Number 05-EPA-2637: The human subjects' research protocol was reviewed by the Institutional Review Board (IRB) of the University of North Carolina; the IRB of Westat, Inc., the IRB of the Henry Ford Health System; and EPA's Human Subjects' Research Review Official.