Gene-environment interactions are the indisputable cause of most respiratory diseases. However, we still have very limited understanding of the mechanisms that guide these interactions. Although the conceptual approaches to environmental genomics were established several decades ago, the tools are only now available to better define the mechanisms that underlie the interaction between these important etiologic features of lung disease. Epigenetic mechanisms can mediate the effect of the environment on the human genome by controlling the transcriptional activity of specific genes, at specific points in time, in specific organs. In this article, we demonstrate the potential importance of epigenetic mechanisms in the development and progression of chronic obstructive pulmonary disease and asthma.