During bone marrow transplantation, hematopoietic stem and progenitor cells (HSPCs) respond to signals from the hematopoietic microenvironment by coordinately activating molecular pathways through Rho GTPases, including Rac. We have previously shown that deletion of Vav1, a hematopoietic-specific activator of Rac, compromises engraftment of transplanted adult HSPCs without affecting steady-state hematopoiesis in adult animals. Here, we show that Vav1-/- fetal HSPCs can appropriately seed hematopoietic tissues during ontogeny but cannot engraft into lethally irradiated recipients. We demonstrate that the engraftment defect of Vav1-/- HSPCs is abrogated in the absence of irradiation and demonstrate that Vav1 is critical for the response of HSPCs to the proinflammatory cytokine interleukin-11 (IL-11) that is upregulated in the marrow of irradiated recipients. Vav1-/- HSPCs display abnormal proliferative responses to IL-11 in vitro and dysregulated activation of pathways critical to engraftment of HSPCs. The engraftment of Vav1-/- HSPCs can be partially rescued in irradiated recipients treated with an anti-IL-11 antibody. These data suggest that HSPCs may respond to different functional demands by selective usage of the IL-11-Vav-Rac pathway, contextualizing further the recent view that HSPCs capable of reconstituting the blood system following transplantation might be distinct from those supporting hematopoiesis during homeostatic conditions. Stem Cells 2018; 36:446-457.