Over the past decade, extracellular nucleotides (such as ATP and UTP) have emerged as key immunomodulators. This family of molecules, already known for its key metabolic functions, has been the focus of intense investigation that has unambiguously shown its crucial role as mediators of cell-to-cell communication. More recently, in addition to its involvement in inflammation and immunity, purinergic signaling has also been shown to modulate BM-derived stem cells. Extracellular nucleotides promote proliferation, CXCL12-driven migration, and BM engraftment of hematopoietic progenitor and stem cells. In addition, purinergic signaling acts indirectly on hematopoietic progenitor and stem cells by regulating differentiation and release of proinflammatory cytokines in BM-derived human mesenchymal stromal cells, which are part of the hematopoietic stem cell (HSC) niche. HSC research has recently blended into the field of immunology, as new findings highlighted the role played by immunologic signals (such as IFN-α, IFN-γ, or TNF-α) in the regulation of the HSC compartment. In this review, we summarize recent reports unveiling a previously unsuspected ability of HSCs to integrate inflammatory signals released by immune and stromal cells, with particular emphasis on the dual role of extracellular nucleotides as mediators of both immunologic responses and BM stem cell functions.