Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. During the past decade, the prevalence of penicillin resistance in S pneumoniae has increased dramatically, with resistance rates approaching 45% in some areas of the United States. Streptococcus pneumoniae has also acquired resistance to other commonly used antimicrobials, including cephalosporins, macrolides, and trimethoprim-sulfamethoxazole. While vancomycin and the newer quinolones are currently highly active against most strains of S pneumoniae, reduced susceptibilities to these agents have been identified in some strains. Prior use of antimicrobial agents is the major risk factor for colonization and infection with antibiotic-resistant strains. beta-Lactam antibiotics remain the treatment of choice for infections caused by susceptible S pneumoniae. The optimum therapy for penicillin-resistant strains remains unclear. Appropriate empirical therapy for patients with community-acquired pneumonia depends in part on the community-specific resistance patterns of S pneumoniae to various antibiotics. In this article, we provide an overview of the development of S pneumoniae resistance to commonly used antibiotics and discuss the implications of the development of resistance on treatment decisions.