Streptococcus pneumoniae is an important pathogen in many community-acquired respiratory infections in the United States and a leading cause of morbidity and mortality worldwide. Unfortunately, S. pneumoniae is becoming increasingly resistant to a variety of antibiotics. Results of recent surveillance studies in the United States show that the prevalence of penicillin-nonsusceptible S. pneumoniae ranges from 25% to >50%, and rates of macrolide resistance among pneumococci are reported to be as high as 31%. A high prevalence of resistance to other antimicrobial classes is found among penicillin-resistant strains. Newer quinolones (e.g., gatifloxacin, gemifloxacin, and moxifloxacin) that have better antipneumococcal activity in vitro are the most active agents and therefore are attractive options for treatment of adults with community-acquired respiratory infections. Efforts should be made to prevent pneumococcal infections in high-risk patients through vaccination.