Forty years after active drug therapy was defined, the treatment of brucellosis still raises the problem of selecting the correct antibiotic and the duration of treatment. Indeed, requirements may be complex since one must select antibiotics which are active in vitro and which diffuse readily into the tissues and into the cells without developing bacterial resistance. Prescriptions must also be long enough, not only to achieve cure, but also to eliminate the Brucella strain. Antibiotics must be found which meet this last criteria yet do not lead to toxic effects or impair the patient's own immune response. Acute septicemic brucellosis in adult men and non-pregnant women has been effectively treated with the following three regimens: 1) doxycycline 200 mg/d and rifampin 900 mg/d orally for 45 days; 2) doxycycline 200 mg/d orally for 45 days and streptomycin 1 g/d IM for three weeks; 3) TMP-SMZ 320-1600 mg/d and rifampin 900 mg/d orally for 45 days. All regimens require a combination of two antibiotics and a prolonged course for total recovery, although casual relapses may occur. The doxycycline-rifampin combination shows the most favorable efficacy/safety ratio, and either antibiotic alone was used successfully in pregnant women by some investigators. The TMP-SMZ-rifampin combination is recommended in children below 8 years of age. Osteoarticular infections can be treated with doxycycline plus rifampin for 3 to 6 months, and streptomycin during the first 2 or 3 weeks. In nervous system complications, the preferred treatment is TMP-SMZ plus rifampin for 3 to 6 months. Brucellar endocarditis should be treated parenterally with streptomycin or gentamycin combined with TMP-SMZ, rifampin and doxycycline, and often requires valvular replacement. Many other antibiotics have been used with good clinical responses in the treatment of brucellosis, e.g., chloramphenicol, erythromycin, ampicillin, and more recently cephalosporins, thienamycin and fluoroquinolones; however, more cases have to be studied before any of these agents is definitely chosen for the treatment of brucellosis.