Epidemiologic studies have clearly shown that air pollution is associated with a range of respiratory effects. Recent research has identified oxidative stress as a major biologic pathway underlying the toxic effect of air pollutants. Genetic susceptibility is likely to play a role in response to air pollution. Genes involved in oxidative stress and inflammatory pathways are logical candidates for the study of the interaction with air pollutants. In this article we use the example of asthma, a genetically complex disease, to address the issue of gene by environment interaction with air pollution. The majority of studies have focused on the genes GSTM1, GSTP1, NQO1, and TNF, but the inconsistency of the results prevents the drawing of firm conclusions. The limited sample size of most studies to date make them underpowered for the study of gene by gene interactions. Large consortia of studies with repeated measurements of environmental exposures and clear phenotypic assessments may help determine special environmental triggers and the window of susceptibility in the development of atopy and asthma. The role of gene by gene interactions and epigenetic mechanisms needs to be considered along with gene by environment interactions.