Lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS) have complex etiologies. It is generally agreed that genetic background has an important role in susceptibility to these diseases, and the genetic contribution to disease phenotypes varies between populations. Linkage analyses have identified some predisposing genes. However, genetic background cannot account for all of the inter-individual variation in disease susceptibility. Interaction between genetic background and exposures to environmental stimuli, and understanding of the mechanisms through which environmental exposure interact with susceptibility genes, is critical to disease prevention. Use of animal models, particularly inbred mice, has provided important insight to understand human disease etiologies because genetic background and environmental exposures can be controlled. We have utilized a positional cloning approach in inbred mice to identify candidate susceptibility genes for oxidant-induced lung injury. Subsequent investigations with cell models identified functional polymorphisms in human homologues that confer enhanced risk of lung injury in humans. This 'bench to bedside' approach may provide an understanding of gene-environment interactions in complex lung diseases is essential to the development of new strategies for lung disease prevention and treatment.