Musculoskeletal infections in children present a diagnostic challenge because they are difficult to recognize in the early stages of the disease and can be confused with other pathology such as tumors or trauma. The severity of disease may be associated with the primary tissue of involvement with bone greater than joint, greater than muscle, greater than soft tissue. The incidence of musculoskeletal infection is higher in infants and young children, and risk factors include premature birth, umbilical catheterization, urinary tract infection, immunodeficiency, and other preexisting disease. Neonates are at greater risk for infection with less virulent organisms due to immaturity of the immune system. The epidemiology of musculoskeletal infection is evolving, and the incidence of musculoskeletal infections in children, especially gram-positive infections, are increasing. Staphylococcus aureus continues to be the leading cause of musculoskeletal infection in children, and the emergence of resistant bacteria such as methicillin-resistant S. aureus is associated with a higher rate of complications. Atypical infections such as tuberculosis have also shown resurgence in the last few decades, whereas other infections such as Haemophilus influenzae are much less prevalent due to widespread immunization. Recent advances in earlier diagnosis and treatment help to reduce complications. However, even when musculoskeletal infection is successfully treated, there may be significant long-term effects on growth.