Ampicillin/sulbactam is an effective solution to the emergence of beta-lactamase-mediated resistance among common pediatric pathogens, and is a widely recognized treatment option for a variety of pediatric infections. Recent antimicrobial surveillance data confirm the continued susceptibility of many Gram-positive and Gram-negative aerobes and anaerobes to ampicillin/sulbactam. Pharmacokinetic studies have demonstrated high drug concentrations at a variety of infection sites, including cerebrospinal fluid and bone. Furthermore, clinical studies have shown that ampicillin/sulbactam, administered intravenously, intramuscularly or orally (as the mutual prodrug sultamicillin), is clinically and bacteriologically effective against upper and lower respiratory tract infections, urinary tract infections, skin, bone and soft-tissue infections, and meningitis, and provides effective surgical prophylaxis. Sultamicillin has an excellent tolerability profile, which is associated with a low rate of treatment discontinuation. Accordingly, ampicillin/sulbactam and sultamicillin should be considered first-choice options for the management of a variety of pediatric infections.