Exposure to air pollution is associated with many diseases, such as asthma, bronchitis, and lung cancer. Despite these adverse health effects, the cellular mechanisms underlying air pollution-associated diseases remain largely unknown. In this study we set out to investigate the genome-wide responses of human lung cells exposed to multiple air pollutant conditions. We first employ a toxicogenomic approach to compare transcripts and molecular networks modulated upon exposure to freshly emitted air pollutants and photochemically altered pollutant mixtures, containing secondary pollutants. The results demonstrate that secondary pollutants initiate a more robust genomic response. After identifying this trend, we investigate potential mechanisms underlying responses to individual secondary pollutants. Here, we evaluate global microRNA expression modifications resulting from formaldehyde exposure. Our analysis reveals that formaldehyde induces significant changes in microRNA levels, which may in turn, regulate genes associated with inflammation and cancer. Together, these investigations reveal novel mechanisms potentially underlying air pollutant-induced disease.