Treatment of bone defects following the debridement of infected skeletal elements can be successfully accomplished using a staged protocol. Dead space management should be initiated using antibiotic blocks or spacers. They provide a local depo of culture-specific antibiotic for infection control as well as a substrate to develop a highly vascularized membrane “pouch.” This pseudo periosteal membrane can then be utilized as a future graft repository. Spacers also provide a means to enhance mechanical stability when incorporated into the fixation construct. Multiple modalities are then utilized to successfully graft into the spacer-induced “pouch.” These include the use of composite graft substitutes (demineralized bone matrix) combined with autogenous cancellous bone graft. Distraction osteogenesis bone transport techniques and free tissue transfer, can be used independently or combined to restore continuity in cases of massive bone loss. The use of these techniques combined with meticulous soft tissue reconstruction and appropriate antibiotic therapy has been shown to successfully treat infected skeletal defects.