In addition to its role as a toxicological signal mediator, the Aryl Hydrocarbon Receptor (AHR) is also a transcription factor known to regulate cellular responses to oxidative stress and inflammation through transcriptional regulation of molecules involved in the signaling of nucear factor-erythroid 2-related factor-2 (Nrf2), p53 (TRP53), retinoblastoma (RB1), and NFκB. Recent research suggests that AHR activation of these signaling pathways may provide the molecular basis for understanding AHR’s evolving role in endogenous developmental functions during hematopoietic stem-cell maintenance and differentiation. Recent developments into the hematopoietic roles for AHR are reviewed, aiming to reconcile divergent findings as to the endogenous function of AHR in hematopoiesis. Potential mechanistic explanations for AHR’s involvement in hematopoietic differentiation are discussed, focusing on its known role as a cell cycle mediator and its interactions with Hypoxia-inducible transcription factor-1 alpha (HIF1-α). Understanding the physiological mechanisms of AHR activation and signaling have far reaching implications ranging from explaining the action of various toxicological agents to providing novel ways to expand stem cell populations ex vivo for use in transplant therapies.