Considerable development of antimicrobial resistance has occurred in the major pediatric bacterial pathogens, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. However, most of the respiratory infections that children suffer are viral and self-limiting, and only a small percentage of them will develop secondary bacterial infections with the pathogens listed. The challenge for rational antibiotic use is to determine which patients can be treated conservatively and which require antimicrobial intervention to avoid prolonged discomfort or development of permanent sequelae. The basis for rational use of antibiotic in the era of resistance in these major pathogens is to avoid overuse of antimicrobial agents, tailor treatment to identified pathogens as much as possible, and base empiric treatment on the disease being treated and the susceptibility of the probable pathogens at breakpoints based on pharmacokinetic and pharmacodynamic parameters. With appropriate dosing regimens based on these parameters and despite development of resistance, amoxicillin is still one of the most active oral agents against S. pneumoniae and non-beta-lactamase producing strains of H. influenzae, whereas amoxicillin-clavulanate is active against beta-lactamase-producing strains of H. influenzae and M. catarrhalis. Parenteral ceftriaxone and oral and parenteral fluoroquinolones are active against all 3 species, but fluoroquinolones should be used with utmost caution when all other options have been considered because of concerns about toxicity and development of resistance. Introduction of a 7-valent conjugate pneumococcal vaccine in the United States in 2000 reduced the prevalence of invasive pneumococcal disease in children younger than 2 years old, but, as of 2001, had not had a major impact on decreasing antimicrobial resistance.