Hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate into all blood lineages. A balance among quiescence, self-renewal, proliferation, and differentiation is precisely maintained to preserve multi-lineage generation throughout the organism's lifetime, and during responses to stress, tissue damage, and pathogens. Although the dysregulation of these processes in HSCs has immense implications for human health, how this balance is regulated is not well understood. Recent data support the novel hypothesis that the aryl hydrocarbon receptor (AhR) is a physiological regulator of HSCs. These data support the contention that AhR acts as a negative regulator by curbing excessive or unnecessary proliferation and promoting HSC quiescence. While our lab has done much work to understand the biology associated with AhR disruption in HSCs, we have not yet identified AhR-regulated signaling pathways that define normal HSC function as well as play a role in altered function under conditions of AhR dysregulation. We hypothesize that the Wnt and/or HIF signaling pathways are critical for AhR-mediated regulation of HSCs. We also hypothesize that dysregulation of AhR expression in HSCs, through disruption of these pathways, results in accumulation of oxidative DNA damage that eventually restricts self-renewal and causes premature senescence. Using a combination of molecular and cell biology techniques, unique animal models, and signaling pathway analyses, we will determin AhR-regulated signaling pathways in HSCs that define AhR function and that may lead to, under conditions of dysregulation, to HSC senescence and hematopoietic disease.