Osteomyelitis in adolescents is a serious disease with the potential for lifelong disability. Microbial invasion of the bone typically results from hematogenous seeding. Staphylococcus aureus is the most common cause of acute hematogenous osteomyelitis. The clinical presentation and management of osteomyelitis in children and adolescents is changing with the emergence of invasive community-acquired methicillin-resistant S aureus infections. Antibiotic treatment should target S aureus including community-acquired methicillin-resistant strains. In some cases, surgical debridement is indicated, especially in cases of chronic osteomyelitis or osteomyelitis associated with septic arthritis. Early diagnosis and subsequent appropriate medical and surgical intervention is critical for avoiding chronic bone destruction and, thus, preventing permanent disability. A multidisciplinary approach involving the pediatrician, infectious disease specialist, and orthopedic surgeon is essential for achieving the best outcome for the patient.