Bone infection requires a multifaceted approach that may be more clearly defined by a pathophysiologic and pathoanatomic classification. Seven types of bone infection are described, which differ by pathophysiology. Anatomically, infection may involve nonmedullary bone tissues, medullary bone, or the epiphyseal growth plate. Treatment can be prescribed accordingly. The isolation and persistence of bone infection usually requires invasion of the septic space by a surgical approach. By this means, bacterial colonization is denied and vascular return can reclaim the tissue domain. Bone infection is difficult to eradicate, yet a proficient surgical approach to sepsis can restore skeletal health and form.