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Hematopoietic homeostasis depends on appropriate self-renewal and differentiation capacity of hematopoietic stem cells. The characterization of the key extracellular signals that integrate with intracellular molecular machinery to regulate hematopoietic stem cells fate choice is crucial to move toward hematopoietic stem cell clinical application.Several factors have been described as positive and negative regulators of hematopoietic stem cell self-renewal and differentiation. Most of the hematopoietic cytokines studied promote either survival or differentiation or both in hematopoietic stem cells ex vivo, whereas morphogens (Wnt, Notch, and Hedgehog) may signify a class of hematopoietic stem cell regulators that support expansion of the hematopoietic stem cell pool by a combination of survival and induced self-renewal.Although Wnt, Notch, and Hedgehog signaling pathways have been implicated in self-renewal and proliferation in vivo, modulation of these pathways alone does not result in substantive expansion of hematopoietic stem cells ex vivo. In addition to these signaling pathways, Bcl-2 family members may have an important role in inducing survival in hematopoietic stem cells both in vivo and ex vivo. Understanding the complex relationship between these unique signaling pathways is essential to achieve successful ex-vivo expansion toward enhanced hematopoietic stem cell transplantation-based therapies.