Processes that regulate quiescence, self‐renewal, and differentiation of hematopoietic stem cells (HSCs) are not well understood. Owing, in part, to the ability of xenobiotic ligands to have persistent effects on the immune system in experimental animals, there has been much work to define a physiological role of the aryl hydrocarbon receptor (AhR) and its relationship to human disease. Persistent AhR activation by dioxin, a potent agonist, results in altered numbers and function of HSCs in mice. HSCs from AhR^−/− knockout (KO) mice are hyperproliferative and have an altered cell cycle. Aging KO mice show characteristics consistent with premature bone marrow exhaustion. We propose that the increased proliferation of HSCs lacking AhR expression or activity is a result of loss of quiescence, and as such, AhR normally acts as a negative regulator to curb excessive or unnecessary proliferation. Similarly, prolonged and/or inappropriate stimulation of AhR activity may compromise the ability of HSCs to sense environmental signals that allow these cells to balance quiescence, proliferation, migration, and differentiation. These data and others support a hypothesis that deregulation of AhR function has an important role in HSC regulation and in the etiology and/or progression of certain hematopoietic diseases, many of which are associated with aging.