Dioxins are ubiquitous environmental challenges to humans, with a pervasiveness that arises from 200 years of rapid industrialization and mechanization of Western societies and which is now extending into the developing world. In spite of their penetrance of the human biota, these compounds are poorly understood in terms of their true physiological potential for harm, and the mechanisms by which they impact cellular and organ level function are only recently becoming clear. Emerging awareness that chronic exposures to toxins may have generational and subtle effects on the outcomes of diseases such as cancer and diabetes, which are already multifactorial and highly complex, creates the context for the current review paper. Here, we summarize dioxin exposure paradigms and the resulting physiological effects that have been documented in animals and humans. Novel insights into potential endogenous end exogenous ligands, as well as the mechanisms by which these ligands impact acute and chronic cellular processes, are discussed. We develop the idea that the diagnosis of dioxin exposure, the subtleties of the cellular effects of the compounds and prognosis of the long-term effects of exposure are problems requiring that researchers leverage the power of genomics and epigenetics. However, the continuation of longitudinal epidemiological studies and the development of a firmer basis from which to extrapolate animal studies will be critical in ensuring optimal insight from these resource-intensive techniques. Copyright © 2012 John Wiley & Sons, Ltd.