Physiologically based pharmacokinetic (PBPK) modeling is an important tool for improving the accuracy of human health risk assessments for hazardous substances in the environment. The proper use of PBPK modeling can reduce uncertainties that currently exist in risk assessment procedures by providing more scientifically credible extrapolations across species and routes of exposure, and from high experimental doses to potential environmental exposures. Current applications of PBPK models range from relatively straightforward uses for the extrapolation of chemical kinetics across species, route, and duration of exposure to much more demanding chemical risk assessment applications requiring a description of complex pharmacodynamic phenomena such as mitogenicity and hyperplasia secondary to cytotoxicity. PBPK modeling helps to identify the factors that are most important in determining the health risks associated with exposure to a chemical, and provides a means for estimating the impact of those factors both on the average risk to a population and on the specific risk to an individual. The chief challenge in the application of PBPK modeling in human health risk assessment lies in the need to generate chemical-specific data to support the development and validation of the models. Extensive use of rapidly developing in vitro and structure-activity relationship techniques is needed to provide the data required for the large number of hazardous chemicals currently contaminating the environment.