This paper describes the evolution of chemical risk assessment from its early dependence on generic default approaches to the current situation in which mechanistic and biokinetic data are routinely incorporated to support a more chemical-specific approach. Two methodologies that have played an important role in this evolution are described: mode-of-action evaluation and physiologically based biokinetic (PBBK) modelling. When used together, these techniques greatly increase the opportunity for the incorporation of biokinetic and mechanistic data in risk assessment. The resulting risk assessment approaches are more appropriately tailored to the specific chemical and are more likely to provide an accurate assessment of the potential hazards associated with human exposures. The appropriate application of PBBK models in risk assessment demands well-formulated statements about the chemical mode of action. It is this requirement for an explicit, mechanistic hypothesis that gives biologically motivated models their power, but at the same time serves as the greatest impediment to the acceptance of a chemical-specific risk assessment approach by regulators. The chief impediment to the regulatory acceptance and application of PBBK models in risk assessment is concern about uncertainties associated with their use. To some extent such concerns can be addressed by the development of generally accepted approaches for model evaluation and quantitative uncertainty analysis. In order to assure the protection of public health while limiting the economic and social consequences of over-regulation, greater dialogue between researchers and regulators is crucially needed to foster an increased use of emerging scientific information and innovative methods in chemical risk assessments.