Inhalation is a common route by which individuals are exposed to toxicants. The air contains a multitude of gases and vapors that are brought into the respiratory tract with each breath. Depending upon the physical and chemical characteristics of the toxicant, the respiratory tract can be considered as a target organ in addition to a portal of entry. Sufficient information is not always available on the fate or effects of an inhaled gas or vapor. Two physiochemical principles, water solubility and reactivity, can be used to predict the site of uptake of gases and vapors in the respiratory tract and potential mechanisms for reaction with respiratory tract tissue and absorption into the blood. Four model compounds, formaldehyde, ozone, dibasic esters, and butadiene are discussed as examples of how knowledge of aqueous solubility and chemical reactivity can help toxicologists predict sites and mechanisms by which inhaled gases and vapors interact with respiratory tract tissues.