Despite improvements in air quality over the past several decades, over 100 million people in the U.S. still live in counties that do not meet the National Ambient Air Quality Standards (NAAQS) for one or more pollutants. During the course of daily living individuals are exposed to multiple pollutants from various sources of both natural and anthropogenic origin. It has become increasingly clear that air pollutant exposure is a risk factor for exacerbation and perhaps even progression of pulmonary and cardiovascular disease. The majority of controlled human exposure studies have examined individual pollutants; however, real-world exposures occur in the context of a complex mixture of pollutants. Different pollutants reach peak levels at different times during the day, which raises the concern that exposure to one pollutant may sensitize an individual so that their response to a subsequent exposure may be enhanced. Thus the sequence of exposure to these agents may affect their relative health effects and result in certain exposure scenarios being more deleterious than others.