The goal of therapy in osteomyelitis is to eradicate established bone infection and to prevent progression into the chronic form. Beta-lactams generally lack organ toxicity or serious side effects when used in high doses for the prolonged intervals necessary to eradicate osteomyelitis. Also, the spectrum of many beta-lactams covers the usual etiologic agents of bone and joint infections. Penetration of beta-lactams into joint fluid is variable but adequate. The significance of measurable "bone levels" is unclear. Staphylococcus aureus in some series accounts for up to 80% of acute haematogenous osteomyelitis, and anti-staphylococcal penicillins and cephalosporins are the drugs of choice in these cases. Other clinical types of osteomyelitis and septic arthritis are associated with a wider range of etiologies. Factors such as the age of the patient (neonates with Gram-negative infections, infants with Haemophilus influenzae arthritis), host defense status (sickle cell patients with Salmonella osteomyelitis) as well as the site of infection (vertebral osteomyelitis associated with UTI), have an increased frequency of causes other than staphylococci, necessitating broader coverage. If environmental contamination has been introduced into the systemic circulation (drug addicts), or into the joint, bone, or contiguous soft tissue (by trauma), the spectrum of causative agents is diverse, and may necessitate concomitant therapy with aminoglycosides and/or anti-anaerobe drugs. As experience is gained with expanded spectrum cephalosporins and carbapenems, their role in the therapy of bone and joint infections will be better defined. Non-beta-lactam antibiotics have been evaluated, but at least for staphylococcal infections should probably be reserved for use in patients with known hypersensitivity or those infected with methicillin resistant or tolerant strains. The development of a non-toxic agent active against these pathogens is a challenge for the future.