Aggregate (multiple pathway) exposures to methyl tertiary-butyl ether (MTBE) in air and water occur via dermal, inhalation, and oral routes. Previously, physiologically based pharmacokinetic (PBPK) models have been used to quantify the kinetic behavior of MTBE and its primary metabolite, tertiary-butyl alcohol (TBA), from inhalation exposures. However, the contribution of dermal and oral exposures to the internal dose of MTBE and TBA were not characterized well. The objective of this study was to develop a multi-route PBPK model of MTBE and TBA in humans. The model was based entirely on blood MTBE and TBA measurements from controlled human exposures. The PBPK model consists of nine primary compartments representing the lungs, skin, fat, kidney, stomach, intestine, liver, rapidly perfused tissue, and slowly perfused tissue. The MTBE and TBA models are linked by a single metabolic pathway. Although the general structure of the model is similar to previously published models of volatile organic compounds, we have now developed a detailed mathematical description of the lung, skin, and gastrointestinal tract. This PBPK model represents the most comprehensive and accurate description of MTBE and TBA pharmacokinetics in humans to date. The aggregate exposure model application for MTBE can be generalized to other environmental chemicals under this framework given appropriate empirical measurement data.