Blood flow and ventilatory flow strongly influence the concentrations of volatile organic compounds (VOCs) in exhaled breath. The physicochemical properties of a compound (e.g., water solubility) additionally determine if the concentration of the compound in breath reflects the alveolar concentration, the concentration in the upper airways, or a mixture of both. Mathematical modeling based on mass balance equations helps to understand how measured breath concentrations are related to their corresponding blood concentrations and physiological parameters, such as metabolic rates and endogenous production rates. In addition, the influence of inhaled compounds on their exhaled concentrations can be quantified and appropriate correction formulas can be derived. Isoprene and acetone, two endogenous VOCs with very different water solubility, have been modeled to explain the essential features of their behavior in breath. This chapter introduces the theory of physiological modeling of exhaled VOCs, with examples of isoprene and acetone.