This review describes the evolution in epidemiologic methods (study design, outcome, and exposure measurements and target population) in relation to knowledge gained concerning the ill-health effects of exposure to grain dust in the workplace over the past three decades. The clinical conditions associated with grain dust exposure are briefly described. Thereafter the study approaches used to investigate grain-related conditions (clinical studies, workforce-based prevalence studies, prevalence studies including unexposed workers, short-term response to exposure, longitudinal studies, supporting evidence from other research arenas, and studies documenting dose-response relationships) are discussed. The objective is to illustrate the strength of sequential, coherent epidemiologic investigation into the ill effects of a particular work environment on human health.