This chapter deals with bone and joint infections. Acute infections of the bone, joint or deep soft tissue require admission. Physicians should initiate the work-up, plan empiric antimicrobial therapy and consult orthopedic surgeon. Prompt diagnostic specimen collection (joint, bone or soft tissue) is necessary to establish the etiology. Combined management with an orthopedic surgeon is essential. Baseline studies include blood culture, wound or needle aspiration for Gram stain, culture and sensitivity and serological markers of inflammation. The clinical manifestations of acute osteomyelitis customarily present subacutely, usually febrile with dull pain and local tenderness and pus, may spread into neighboring joint. Indium-labeled white blood cell (WBC) scans have been used in the setting of orthopedic implants as a means of avoiding distortion of MRI and CT scans by metal artifacts. In patients with prosthetic joint infections with no systemic or severe local signs of infection and in whom the prosthesis is not loose or surgery is not possible or desired, lifelong oral antimicrobial therapy may be considered to suppress the infection and retain usefulness of the total joint replacement.