Fracture healing is an extremely complex interaction of cells, biologic pathways, and molecules. Certainly, the inflammatory response is one of the initiating factors for bone healing. The inflammatory phase is a critical period characterized by low oxygen tension, impaired perfusion, and the migration of a wide array of cells and release of active molecules. Systemwide inflammatory conditions also modulate the primary processes of fracture management. Osteoprogenitor cells, mesenchymal cells, osteoblasts, and chondrocytes contribute to the healing and inflammatory response at the bone level. The inflammatory process is dependent on and propagates through proinflammatory cytokines, the transforming growth factor-β superfamily with other growth factors, and the metalloproteinases and angiogenic factors. Interference with any of these pathways or proteins either promotes or more likely decreases fracture healing. This article reviews the initial inflammatory response to trauma as it pertains to musculoskeletal healing.