Osteomyelitis is a common and challenging condition for hospitalists to manage. The 3 main types of osteomyelitis that are commonly seen in the hospital setting are 1) contiguous spread from decubitus or diabetic ulcers, 2) hematogenous spread, such as in vertebral or long bone metaphyses, and 3) infections associated with a prosthetic joint. In patients with diabetes, osteomyelitis is the underlying cause of about 20% of foot infections, and greatly increases the chance that the patient will eventually need an amputation and be subject to perioperative risks. Osteomyelitis from hematogenous spread is increasing. The prevalence of vertebral osteomyelitis is also increasing, particularly in intravenous drug users and patients treated with immune-modulating agents. Prosthetic joint infections are perhaps the most challenging type to treat, and require hospitalists, orthopedic surgeons, and infectious disease specialists to work closely together to plan for effective treatment. Due to increasing antibiotic resistance, the microorganisms involved are also proving more difficult to treat. Emerging resistance to the commonly used antibiotics is resulting in changes in treatment choices. Community-acquired methicillin-resistant Staphylococcus aureus is commonly seen, and there is increasing concern about emerging vancomycin resistance. Treatment of osteomyelitis is still based largely on expert opinion rather than evidence from controlled studies.