Ceftriaxone is an effective and safe agent for the treatment of osteomyelitis. It is active against most of the causative organisms. Combined with surgery, it is useful for all types of osteomyelitis. In addition, its once-daily dosing has made outpatient therapy feasible for most patients. Questions that remain are whether full treatment with 2 gm every 24 hours for four to six weeks is needed for osteomyelitis or whether 1 gm/day would provide comparable results. The relevance of minimal inhibitory/bactericidal concentrations and serum inhibitory/bactericidal concentrations has not been-determined. Some questions remain about the cure rate of ceftriaxone against S. aureus osteomyelitis, although most cases do well. Comparative studies with agents such as cefazolin or oxacillin would be helpful to resolve this issue. Long-term follow-up of patients treated for osteomyelitis outcome has not been done in sufficient detail to be certain of the comparative results of different antimicrobials. The success rate of the quinolones against gram-negative osteomyelitis appears good, but their activity against gram-positive organisms is uncertain, and development of resistance is a problem. Questions still linger in regard to how much can be accomplished with antimicrobial therapy without surgery and how long antimicrobials are needed once effective surgery has been performed.