Abstract: In the 1700s, Bernardino Ramazzini was among the first to describe respiratory disease among agricultural workers. Since then, farmers continue to have higher rates of respiratory illnesses, even as changes occur in occupational and environmental exposures on farms. While grain and animal exposures have been well studied for their role in agricultural lung diseases, pesticide exposures have not. Using the Agricultural Health Study, a prospective cohort study of ∼89,000 licensed pesticide applicators and their spouses in Iowa and North Carolina, we are currently assessing the association of pesticides with respiratory outcomes, including wheeze, adult asthma, farmer's lung, and chronic bronchitis. At enrollment (1993–1997), 19% of farmers and 22% of commercial pesticide applicators reported wheeze in the previous year. Using logistic regression models adjusted for age, state, smoking status, and body mass index, we evaluated the association of 40 individual pesticides with wheeze within these two groups separately. In both groups, we observed strong evidence of an association of organophosphates with wheeze. For farmers, the organophosphates chlorpyrifos, malathion, and parathion were positively associated with wheeze; for the commercial applicators, the organophosphates chlorpyrifos, dichlorvos, and phorate were positively associated with wheeze. Chlorpyrifos was strongly associated with wheeze in a dose-dependent manner in both groups; use of chlorpyrifos for at least 20 days per year had an odds ratio of 1.48 (95% confidence interval [CI]= 1.00–2.19) for farmers and 1.96 (95% CI = 1.05–3.66) for commercial applicators. Our wheeze results are consistent with recent animal models that support a role for organophosphates and respiratory outcomes.