In the past decade, the incidence of methicillin-resistant Staphylococcus aureus infections in children has increased. This phenomenon has led to a rise in complex, deep infections involving the musculoskeletal system for which a comprehensive approach of evaluation and treatment has become necessary. Whenever possible, cultures should be obtained to guide specific antibiotic selection. The potential for infections involving multiple tissue locations within the same patient and the risk for complications such as deep vein thrombosis necessitate a thorough, often multidisciplinary, approach in the care of these children. MRI is valuable in defining the anatomic and spatial extent of infection as well as in guiding the decision and approach for surgery. Most patients have favorable outcomes with sequential parenteral to oral antibiotic therapy after adequate surgical débridement of the infection. Close outpatient follow-up is essential to ensure antibiotic compliance and to identify late consequences of the infection.