Musculoskeletal infections, including osteomyelitis and septic arthritis, pose significant challenges due to poor antibiotic penetration, biofilm formation, and rising antimicrobial resistance. This chapter outlines the burden of surgical site infections, principles of antimicrobial susceptibility testing, and the classification and application of prophylactic, empirical, and definitive therapies. Key antibiotics such as vancomycin, piperacillin-tazobactam, cefuroxime, and carbapenems are reviewed with respect to dosage, indications, and pharmacokinetics. The chapter emphasizes factors affecting treatment efficacy, including tissue penetration and host-specific considerations. It also highlights recent FDA-approved antibiotics targeting multidrug-resistant organisms and underscores the importance of antibiotic stewardship and multidisciplinary care. Emerging strategies focused on local drug delivery, optimized pharmacodynamics, and biofilm disruption are discussed to improve outcomes in managing bone and joint infections.