A physiologically based pharmacokinetic model was developed and used to describe the pharmacokinetics of benzene in three species: mice, rats, and humans. For each species, the body was divided into five anatomical compartments, consisting of liver, fat, bone marrow, and muscle, and organs such as brain, heart, kidney, and viscera, connected by the arterial and venous blood flow pathways. Metabolism of benzene followed Michaelis-Menten (nonlinear) kinetics in all species and occurred primarily in the liver compartment and, to a lesser extent, in the bone marrow. Comparison of model results with empirical data on inhalation, gavage, and intraperitoneal and subcutaneous injection in mice, rats, and humans, demonstrates the utility of a physiological pharmacokinetic model in describing the pharmacokinetics of benzene in three species across multiple routes of exposure.