Understanding the pathophysiology and basic mechanisms of asthma and chronic obstructive pulmonary disease (COPD) has been an intense source of investigation over the years. For decades, research in these fields has focused on the control of inflammation. However, new evidence has emerged demonstrating that airway inflammation is just the surface of a more complex pathobiological relationship between the disease and its host. Specifically, the relationship is a unique interaction of one's genetic background and the environment. The airway response to inhaled endotoxin serves as an effective model for studying the pathobiology of asthma as well as the importance of host genetic susceptibility. In this review, we provide a brief overview on the role of endotoxin in asthma and COPD, highlighting a few of the major discoveries, but also discussing future directions.