Toxicokinetic models are not constrained by assumptions of equilibrium as are thermodynamic (equilibrium-partitioning) models and are more accurate predictors of toxicant accumulation for non-steady-state exposures and multiple uptake routes. Toxicokinetic models – compartment-based models, physiological-based models, and energetics-based models – are reviewed and the different mathematical formalisms compared. Additionally, the residue-based toxicity approach is reviewed. Coupling toxicokinetic models with tissue concentrations at which toxicity occurs offers a direct link between exposure and hazard. Basing hazard on tissue rather than environmental concentrations avoids the errors associated with accommodating multiple sources, pulsed exposures, and non-steady-state accumulation.