Staphylococcus aureus is able to infect virtually all organ systems and is a frequently isolated etiologic agent of osteomyelitis, a common and debilitating invasive infection of bone. Treatment of osteomyelitis is often unsuccessful due to extensive pathogen-induced bone damage that can limit antibiotic penetration and immune cell influx to the infectious focus. S. aureus triggers profound alterations in bone remodeling in a murine model of osteomyelitis, in part through the production of osteolytic toxins. However, staphylococcal strains lacking osteolytic toxins still incite significant bone destruction, suggesting that host immune responses are also major drivers of pathologic bone remodeling during osteomyelitis. The objective of this dissertation was to identify host immune pathways that contribute to antibacterial immunity during S. aureus osteomyelitis, and to define how these immune responses alter bone homeostasis and contribute to bone destruction. We hypothesized that MyD88-dependent immune pathways are important for control of bacterial burdens in bone, but these same pathways may negatively impact bone remodeling during S. aureus osteomyelitis by promoting osteoclastogenesis and bone loss. We specifically focused on the adapter protein MyD88 and MyD88-dependent receptors: interleukin-1 receptor (IL-1R) and toll-like receptors TLR2 and TLR9, given their antibacterial roles as and their potential to mediate osteo-immunologic crosstalk. The adapter protein MyD88 was found to be critical for local control of bacterial burdens, and for prevention of bacterial dissemination and death following osteomyelitis. While TLR2 and TLR9 were not found to contribute to the control of bacterial burdens at later time points, we discovered that IL-1R signaling is necessary for local control of bacterial replication during osteomyelitis. We also demonstrate that S. aureus enhances osteoclastogenesis in vitro and increases the abundance of osteoclasts in vivo. This increase in osteoclast abundance occurs alongside dramatic trabecular bone loss, and is dependent on intact IL-1R signaling. Collectively, these data define MyD88 and IL-1R as critical components of the host response to S. aureus osteomyelitis, but also demonstrate that IL-1R-dependent immune responses trigger collateral bone damage through activation of osteoclast-mediated bone resorption.