Bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) can be activated by type I IFNs, TLR agonists, viruses, and bacteria to increase hematopoiesis. In this study, we report that endotoxin treatment in vivo induces TLR4, MyD88, and Toll/IL-1 resistance domain-containing adaptor-inducing IFN-β (TRIF)-dependent expansion of BM HSPCs. Bacterial infection by Staphylococcus aureus or cecal ligation and puncture also induces HSPC expansion, but MyD88, TRIF, type I IFN, cytokine, PG, or oxidative stress pathways are not required for their expansion. S. aureus-induced HSPC expansion in MyD88−/− TRIF−/− mice is also normal, but is associated with BM remodeling as granulocyte stores are released peripherally. Importantly, reduction in BM cellularity alone can reproduce HSPC expansion. These data show in vivo HSPC responses to bacterial infection are complex and not absolutely dependent upon key inflammatory signaling pathways.