Cadmium (Cd) occurs in low concentrations in all human diets and in cigarettes. In contaminated areas and in certain occupations, high human exposures occur. In assessing risk to human health, it is important to identify the adverse effect that occurs at the lowest exposure level, i.e., the critical effect, which is crucial for preventive action. Excessive Cd exposure may give rise to renal, pulmonary, hepatic, skeletal, reproductive effects, and cancer. Previous evaluations (e.g., by WHO) have identified renal dysfunction, occurring in long‐term Cd exposure, as the critical effect. However, skeletal and reproductive effects are also discussed as possible critical effects. For preventive action, information is important about exposure levels that give rise to the earliest (critical) effects. To gain new information on this issue, population groups in China exposed to high concentrations of Cd via rice and Cd‐exposed workers were studied for possible renal, skeletal, and male reproductive toxicity. Skeletal effects in terms of decreased bone mineral density and an increased occurrence of fractures were found in groups of the general population living in the most Cd‐exposed area. Our studies further show that renal effects measured by sensitive biomarkers, such as urinary content of beta‐2‐microglobulin, calcium, and N‐acetyl‐beta‐D‐glucosaminidase, occurs at lower cumulative exposures to Cd than those giving rise to skeletal effects and also at lower exposures than previously estimated, e.g., by WHO. The findings confirm the renal dysfunction as the critical effect of long‐term Cd exposure. Metallothionein (MT) gene expression in peripheral blood lymphocytes was measured in Cd exposed workers. A higher prevalence of renal dysfunction was found among Cd exposed workers with low MT gene expression than among those with high MT gene expression, at similar blood and urinary Cd levels. MT gene expression in PBLC thus may be a biomarker for identifying sensitive population groups. J. Trace Elem. Exp. Med. 16:307–319, 2003. © 2003 Wiley‐Liss, Inc.