As we develop a better understanding of the adverse effects of the indoor environment on health, the pathophysiologic mechanisms contributing illnesses caused by indoor environmental factors will become more clearly defined. The term building-related illness applies to those adverse health effects for which we have a well-defined link between environmental agents in a specific building and the resultant health disorders. This class of illnesses frequently involves the skin and respiratory tract because of the ease with which indoor environmental contaminants come in contact with these tissues. Agents that cause building-related illnesses generally induce illness by one of four mechanisms: (1) immunologic, (2) infectious, (3) toxic, or (4) irritant. Some agents may work through more than one mechanism. This article discusses the different mechanisms that cause building-related illness, the different types of this class of illnesses, and the evidence validating the connection between the environmental agents and the diseases they cause.