Increasing antimicrobial resistance among respiratory pathogens has the potential to reduce the efficacy of standard dosage regimens for many oral drugs. The goal of antimicrobial therapy is to maximize bactericidal activity. The duration of time that serum concentrations exceed the MIC is the pharmacokinetic/pharmacodynamic parameter that determines efficacy for beta-lactams, macrolides, and trimethoprim/sulfamethoxazole. Studies in animal models suggest that serum levels of beta-lactams need to exceed the MIC for about half of the dosing interval to obtain maximum antimicrobial efficacy. Studies in children with acute otitis media also demonstrate that serum concentrations need to exceed the MIC for 40% or more of the dosing interval to obtain bacteriologic cure in over 85% of patients. With the oral beta-lactams used against penicillin-resistant Streptotoccus pneumoniae, this goal is obtained only with amoxicillin and amoxicillin/clavulanate. For Haemophilus influenzae, several beta-lactams including cefixime, cefpodoxime, and amoxicillin/clavulanate provide serum levels with the longest durations above the MIC. Antimicrobial resistance has also stimulated the search for new potent antimicrobials, altered but effective dosing regimens, and resistance control measures, such as the prudent use, optimal infection control practices, and vaccines to reduce colonization and subsequent infection.