Extremity pain is one of the most common pediatric medical complaints. Creating a list of possible causes of pediatric extremity pain is based off history and physical exam. Important information to obtain from the patient’s history include time of pain onset, location of pain, quality of pain, history of trauma, and patient’s medical history. The differentials for extremity pain and/or joint swelling are broad and can include trauma, inflammatory, and infection. Osteomyelitis and septic arthritis are two types of musculoskeletal infections. Septic arthritis is an infection of the synovial space that involves the lining and fluid of a joint. Osteomyelitis is an infection of the bone itself. This chapter will present two cases of children with musculoskeletal infections and discuss the initial assessment and management utilizing and evidence-based approach.