Individual variation in susceptibility to chemical toxicity may be due to differences in toxicokinetic patterns or effect modification. Well-documented interspecies genetic differences in susceptibility to chemicals had lead to studies of such variation also within species. Epidemiological evidence now suggests that common variations, particularly in the P-450 enzymes, may play a major role in determining individual susceptibility to chemically-induced disease. Physiologic factors are involved in the particular susceptibility of the fetus, the newborn, and the old. Constitutional susceptibility is also affected by acquired conditions, including chronic disease, such as diabetes mellitus. Perhaps the most complex area relates to the increase in vulnerability caused by previous or contemporary exposure to other factors, thus eliciting, e.g., synergistic effects. Although amply demonstrated by experimental studies, epidemiological or clinical confirmation is generally lacking. One hypothesis suggests that a chemical exposure may affect the reserve capacity of the body, though not resulting in any immediate adverse effect. Subsequently, the body becomes unable to compensate for an additional stress, and toxicity then develops. Epidemiological approaches are available and need to be expanded. Research in this area has potential ethical implications which should be dealt with in an open, informed forum.