Bone and joint infections are potentially limb-threatening or even life-threatening diseases. Emergency physicians must consider infection when evaluating musculoskeletal complaints, as misdiagnosis can have significant consequences. Patients with bone and joint infections can have heterogeneous presentations with nonspecific signs and symptoms. Staphylococcus aureus is the most commonly implicated microorganism. Although diagnosis may be suggested by physical examination, laboratory testing, and imaging, tissue sampling for Gram stain and microbiologic culture is preferable, as pathogen identification and susceptibility testing help optimize long-term antibiotic therapy. A combination of medical and surgical interventions is often necessary to effectively manage these challenging infections.