Understanding the pathophysiology of posttraumatic osteomyelitis is crucial as researchers attempt to meet the challenge of developing more effective strategies for the management and prevention of this infection. Some aspects of pathogenesis have been well described, including the important roles of the extent of soft tissue injury, bacterial attachment to necrotic bone and fixation devices, and bacterial contamination at the time of injury. More recently, the importance of early wound coverage in preventing osteomyelitis has been emphasized. Now some of the cellular interactions that promote infection and tissue damage are beginning to be understood. Trauma can have deleterious effects on host response to infection through its activation of certain cytokines. These cytokines, mainly produced by cells of the immune system, regulate the action of polymorphonuclear leukocytes, macrophages, and lymphocytes. Bacteria have been shown to use diverse tactics to initiate and maintain infection that lead to host defense impairment, decreased efficacy of antibiotics, and direct tissue damage. New insights into the pathophysiology of osteomyelitis may lead to the innovative therapeutic approaches needed to improve the standard of care for this infection.