Hematopoietic stem and progenitor cells (HSPCs), as well as other types of stem cells, circulate under steady-state conditions at detectable levels in peripheral blood (PB), with their numbers increasing in response to stress, inflammation and tissue/organ injury. This mobilization process may be envisioned as a danger-sensing response mechanism triggered by hypoxia or mechanical or infection-induced tissue damage that recruits into PB different types of stem cells that have a role in immune surveillance and organ/tissue regeneration. Mobilization is also significantly enhanced by the administration of pharmacological agents, which has been exploited in hematological transplantology as a means to obtain HSPCs for hematopoietic reconstitution. In this review we will present mounting evidence that innate immunity orchestrates this evolutionarily conserved mechanism of HSPC mobilization.