Thorough surgical debridement and intelligent use of antibiotics are key factors in the treatment of implant-associated bone infections and osteomyelitis. The local use of antibiotics is intended to achieve high concentrations of the antimicrobial agents in the wound for eradication of the bacteria or at least to reduce the bacterial load combined with low systemic concentrations to eliminate systemic side effects. Moreover, it enables access to necrotic and devascularized infected bone fragments in the wound which cannot be reached by intravenous therapy. The intention of this article is to review different antibiotics and carrier systems to provide a practical guideline for the intraoperative use of these agents for the surgeon. Gentamicin, tobramycin, and vancomycin are the most frequently used antibiotics in septic orthopedic surgery. However, only rifampicin offers the combination of antibiofilm activity and intracellular activity against Staphylococcus aureus, however, its use in combination with polymethylmethacrylate (PMMA) is compromised due to the interference with PMMA polymerization. In general, there are resorbable and nonresorbable carriers which offer different antibiotic loading options. PMMA is the most common nonresorbable carrier for which commercial products, such as beads or antibiotic-loaded spacer cements are available. Different antibiotic loadings for handmade PMMA delivery systems have been described in the literature including antifungal agents. Resorbable carrier systems lead to a material-tissue interaction with subsequent degradation of the material and do not require removal by an additional surgical procedure. Collagen-based, calcium sulfate–based, and calcium phosphate–based materials are typical biodegradable carriers that can be used for the local delivery of antibiotics.