Gram-positive organisms, particularly staphylococci and streptococci, are responsible for the majority of bone and joint infections. Treatment of these infections can be difficult, usually involving a prolonged course of antibiotics, often with surgical intervention. The selection of antibiotics depends on sensitivity profile, patient tolerance and long-term goals, e.g. cure or suppression, but there are few randomized controlled trials in patients comparing efficacy of different antibiotics. Different degrees of bone penetration and clinical outcome for specific antibiotics, e.g. the beta-lactams, clindamycin and quinolones, have been described, although the methodology in these studies is not standardized and findings cannot always be applied directly to patients. The effect of attaining minimum serum bactericidal concentrations in patients has also been studied but this is no longer routinely recommended in clinical practice. Comparative clinical trials are few but have demonstrated efficacy of oral fluoroquinolones in combination with either rifampicin or fusidic acid for selected Gram-positive infections. In the past decade, increasingly resistant organisms, e.g. methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci have been recognized as causes of orthopaedic infection. Individual case reports describe successful treatment using the newer antibiotics, e.g. linezolid and quinupristin/dalfopristin, but results of clinical trials are awaited.