Acute respiratory health effects in children from exposure at current ambient levels of ozone are well documented; however, evidence for acute effects from other criteria pollutants such as nitrogen dioxide and respirable particles is inconsistent. Whether chronic effects result from long-term exposure to any of these pollutants during childhood is an important unresolved question. Establishing whether acute or chronic effects result from childhood exposure and identifying sensitive subgroups may require integration of biologic mechanisms of lung defenses, injury, and response into the study design and statistical models used in analyses. This review explores the theoretical basis for explaining such adverse effects in light of our contemporary understanding of mechanisms of lung injury and response at the cellular and molecular levels. The rapidly evolving understanding of the effects of air pollution on cellular and molecular levels presents an opportunity to develop and refine innovative biologically based hypotheses about the effects of childhood exposure. We hypothesize that children with low fruit and vegetable intake, low antioxidant levels, high polyunsaturated fat intake, or who have inherited certain alleles for genes involved in lung defenses and immune response regulation may be at increased risk for adverse effects. Because responses to air pollutants of interest are complex and involve a number of pathophysiologic processes, the magnitude of main effects of dietary factors, genes, and gene-environment interactions may be modest for individuals; however, each may make an important contribution to the population burden of preventable respiratory diseases.