Intercellular communication networks maintain homeostasis and coordinate regenerative and developmental cues in multicellular organisms. These constitute local juxtacrine and paracrine signaling for within-tissue cellular regulation, and systemic endocrine signaling for organism-level interactions. Adult or tissue-resident stem cells, while normally quiescent, are activated under appropriate circumstances, giving rise to a hierarchy of increasingly differentiated progenitors, thereby regenerating damaged tissue. Intercellular networks are of particular relevance for stem cell biology as stem and progenitor cell fate must be dynamically responsive to physiological demand and external perturbations. For example, adult blood stem cell fate decisions in vivo are regulated via interactions within the bone marrow microenvironment—the stem cell ‘niche’. Recent progress has been made in elucidating the physical location and cellular components of this niche, including molecular cross-talk between hematopoietic stem cells (HSCs) and niche cells (Kiel and Morrison, 2008). However, local interactions within the microenvironment are insufficient to explain the dynamic responsiveness of tissue-resident stem cells to systemic signals (Mayack et al, 2010). Numerous studies have indirectly demonstrated hematopoietic stem and progenitor cell fate as responsive to systemic perturbations such as bleeding and irradiation via (undefined) feedback signaling from mature cells (Kirouac and Zandstra, 2006). Such regulatory mechanisms appear to be a conserved feature in other adult stem cells, including neural and epithelial tissues (Lander et al, 2009).