Skeletal infections in injection drug users have an insidious onset, present with indolent symptoms, and often occur in unusual locations. Unless physicians are familiar with the disease entities unique to the injection drug user, the diagnosis is frequently delayed. Systemic signs of infection are often lacking. The organisms causing the infection represent a wide spectrum; hence, empiric therapy is not generally recommended. Plain-film radiographs are of little help for early diagnosis. Imaging studies, especially radionucleotide studies and CT or MR imaging scans, can help localize the site of infection. For etiologic diagnosis of these infections, bone biopsy or needle aspiration of the involved bone or joint is required. The choice of antibiotic agent should be based on culture results and the antimicrobial susceptibility of the causative organism. Treatment may also involve surgical drainage or débridement of affected structures. Failure to manage acute bone and joint infection aggressively inevitably leads to chronic, often incurable, infection. Successful therapy requires a team approach including the internist and consultants from orthopedic surgery, infectious diseases, and substance abuse counselors.