To review and evaluate whether the investigation of disease clusters continues to play an important role in establishing disease-toxin connections in the workplace, 87 original disease cluster reports were identified that established disease-toxin connections in occupational medicine (from 1775 to 1990). Four advantages of the workplace with regard to cluster discovery and investigation were identified: natural denominator boundaries, shared exposures, the ability to form intermediate hypotheses, and the possibility of locating comparable populations in which to study these hypotheses. Because new products, intermediate products, and procedures are introduced into working environments faster than epidemiologic and toxicologic studies can be designed to evaluate their potential risks, disease cluster investigations will remain central to the understanding of disease, and to protecting workers.