Occupational and environmental exposure to grain dust can cause a spectrum of clinical syndromes, including asthma, acute and chronic changes in airway reactivity, grain fever, bronchitis, and progressive irreversible airflow obstruction. Exposure-response studies have shown that declines in lung function across the workshift are directly related to higher ambient concentrations of grain dust. Although the pathogenesis of grain dust-induced airway disease is not known, several lines of evidence indicate that the physiologic response to grain dust is primarily mediated by an acute non-allergic inflammatory response in the lower respiratory tract. Our results indicate that grain dust-induced lung disease is primarily caused by endotoxin and that the alveolar macrophage, airway epithelia, and specific proinflammatory cytokines appear to be particularly important in the initial inflammatory response. Several lines of evidence will be presented supporting these findings. First, we will examine the physiologic and biologic response to inhaled grain dust and directly compare this response to the physiologic and biologic response to inhaled endotoxin. Second, we will present results from studies in which we have modified the concentration of endotoxin in the bioaerosol to determine the effect that this has on the inflammatory response to grain dust. Third, we will present data from studies in which we modified the ability of the host to respond to endotoxin and determined whether this affects the inflammatory response to grain dust. Finally, we will present findings from our genetic studies investigating the genetic basis for endotoxin hyporesponsiveness.