Osteomyelitis, or infection of the bone and marrow, is associated with significant morbidity. The incidence of osteomyelitis is increasing, particularly relating to complications from diabetic foot infections. Staphylococcus aureus is the most frequent pathogen, but other organisms may be involved. The primary route of infection is through hematogenous spread. The pathogenesis involves several factors, including pathogenic factors (bacterial virulence, biofilm formation, antibiotic resistance), host factors (local issues including vascular compromise or systemic conditions related to diabetes or immunosuppression), and environmental factors (variations in vascular structures or the presence of an implant). The transition from acute osteomyelitis to chronic osteomyelitis is characterized by the formation of intraosseous abscesses, the development of necrosis of the cortical bone leading to sequestrum formation, and the formation of new bone (involucrum) in the presence of draining sinus tract. Diagnosis consists of clinical history (localized pain, presence of fever, presence of sinus tract), along with imaging studies. Plain X-ray films may show changes at a later stage, whereas CT scans can often present the sequestrum and involucrum, and MRI has the greatest sensitivity and specificity for detecting infection. Further, radiolabeled imaging (radionuclide scans) or PET-CT can be acquired if suggested studies are not conclusive. Across the spectrum of care, management is multidisciplinary. Management typically involves aggressive surgical intervention (debridement or removal of infected and/or necrotic tissues) and directed antibiotic therapy. Surgical techniques address soft tissue and bone loss, ranging from skin grafting and muscle flaps to complex reconstruction of bone, including bone transport, the Masquelet technique, and antibiotic-impregnated cement spacers or megaprostheses. In the most severe cases where surgical options leave a limb unmanageable, amputation may be considered. General management of osteomyelitis involves pain control, nutritional support, and wound care. Advances in recent years have also focused on an understanding of osteoclastic activity, anti-biofilm mechanisms, and drug delivery systems.