Functional biological markers of environmental exposures are important in epidemiological studies of disease risk. Such markers not only provide a measure of the exposure, they also reflect the degree of physiological and biochemical response to the exposure. In an observational study, using DNA microarrays, we show that it is possible to distinguish between 85 individuals exposed and unexposed to tobacco smoke on the basis of mRNA expression in peripheral leukocytes. Furthermore, we show that active exposure to tobacco smoke is associated with a biologically relevant mRNA expression signature. These findings suggest that expression patterns can be used to identify a complex environmental exposure in humans.