Infections of bone occur in a variety of clinical settings, ranging from spontaneous isolated infections arising from presumed hematogenous spread to those associated with skin and soft tissue wounds or medical implants. The majority are caused by the ubiquitous bacterium Staphyloccocus (S.) aureus, which can exist as a commensal organism on human skin as well as an invasive pathogen, but a multitude of other microbes are also capable of establishing bone infections. While studies of clinical isolates and small animal models have advanced our understanding of the role of various pathogen and host factors in infectious osteomyelitis (iOM), many questions remain unaddressed. Thus, there are many opportunities to elucidate host-pathogen interactions that may be leveraged toward treatment or prevention of this troublesome problem. Herein, we combine perspectives from bone biology and microbiology and suggest that interdisciplinary approaches will bring new insights to the field.