Endocannabinoids are lipid mediators that signal via several seven-transmembrane domain G protein-coupled receptors. The endocannabinoid receptor CB2 is expressed on blood cells, including stem cells, and mediates the effects of cannabinoids on the immune system. The role of the endocannabinoid system in immature hematopoiesis is largely elusive. Both direct effects of endocannabinoids on stem cells and indirect effects through endocannabinoid-responsive niche cells like macrophages have been reported. Using two different CB2-deficient mouse models, we studied the role of the endocannabinoid system in immature hematopoiesis. Moreover, we utilized both models to assess the specificity of putative CB2 agonists. As heterodimerization of CB2 and CXCR4, which is highly expressed on hematopoietic stem cells, has already been described, we also assessed potential consequences of CB2 loss for CXCR4/CXCL12 signaling. Overall, no differential effects were observed with any of the compounds tested; the compounds barely induced signaling by themselves, whereas they attenuated CXCL12-induced signals in both CB2-competent and CB2-deficient cells. In vivo experiments were therefore by necessity restricted to loss-of-function studies in knockout (CB2–/–) mice: Except for mild lymphocytosis and slightly elevated circulating progenitor cells, homeostatic hematopoiesis in CB2–/– mice appears to be entirely normal. Mobilization in response to pharmacological stimuli, Plerixafor or G-CSF, was equally potent in wild-type and CB2–/– mice. CB2–/– bone marrow cells reconstituted hematopoiesis in lethally irradiated recipients with engraftment kinetics indistinguishable from those of wild-type grafts. In summary, we found the endocannabinoid system to be largely dispensable for normal murine hematopoiesis.