Humans are exposed to a large number of environmental chemicals: Some of these may be toxic, and many others have unknown or poorly characterized health effects. There is intense interest in determining the impact of exposure to environmental chemical mixtures on human health. As the study of mixtures continues to evolve in the field of environmental epidemiology, it is imperative that we understand the methodologic challenges of this research and the types of questions we can address using epidemiological data. In this article, we summarize some of the unique challenges in exposure assessment, statistical methods, and methodology that epidemiologists face in addressing chemical mixtures. We propose three broad questions that epidemiological studies can address: a ) What are the potential health impacts of individual chemical agents? b ) What is the interaction among agents? And c ) what are the health effects of cumulative exposure to multiple agents? As the field of mixtures research grows, we can use these three questions as a basis for defining our research questions and for developing methods that will help us better understand the effect of chemical exposures on human disease and well-being.