Oral cephalosporins, after 25 years of use, continue to present the clinician with a therapeutic challenge. The older agents have been extensively prescribed for ambulatory adult and pediatric patients with a wide variety of infections caused by gram-positive and some gram-negative organisms. The newer agents, cefaclor, cefuroxime axetil, and cefixime, have increased in vitro activity against beta-lactamase-secreting strains of Haemophilus influenzae and Branhamella catarrhalis which has made them more popular for the treatment of otitis media and respiratory tract infections in children. The new agents are also more active against most gram-negative organisms. However, clinical trials have failed to show a clear-cut superiority over older, proven therapy when used to treat infections of the respiratory tract, middle ear, skin and soft tissue, urinary tract, and bone and joints when caused by sensitive organisms. Published reports of clinical trials continue to support the recommendation that oral cephalosporins, especially the newer and more expensive agents, be reserved for second- or third-line therapy when amoxicillin, penicillin V, or trimethoprim/sulfamethoxazole have either failed or produced patient intolerance. Erythromycin/sulfisoxazole and amoxicillin/clavulanate potassium are equally efficacious and also less expensive than cefaclor, cefuroxime axetil, and cefixime and could be considered second-line therapy prior to the use of the newer cephalosporins for infections in the ambulatory patient.