The epidemiology, resistance mechanisms, susceptibility testing, treatment, prevention, and clinical importance of penicillin-resistant Streptococcus pneumoniae (PRSP) infection are discussed. PRSP is an established presence in the United States, with some geographic areas reporting decreased susceptibility in up to half of isolates. The mechanism of resistance to beta-lactam antibiotics in S. pneumoniae is genetic changes resulting in decreased binding of drug to the bacterial cell wall. Emerging PRSP strains have necessitated testing as a tool in selecting drugs for treating life-threatening infections. Opinions differ on how to treat these infections empirically. Non-life-threatening infections, such as otitis media, are still often treated successfully with amoxicillin, amoxicillin-clavulanate potassium, or a third-generation cephalosporin. Currently recommended initial treatment of pneumococcal pneumonia in otherwise healthy patients requiring hospitalization consists of cefuroxime, ceftriaxone, or cefotaxime; some authors continue to emphasize injectable penicillin. Once the mainstay of empirical treatment of pneumococcal meningitis, penicillin has largely been abandoned in favor of cefotaxime or ceftriaxone. Vaccination remains an underutilized strategy in atrisk populations. The clinical importance of penicillin resistance among pneumococci is still uncertain. Changing patterns in the susceptibility of S. pneumoniae to penicillin make selection of appropriate therapy increasingly difficult. Key considerations are the site of infection and the level of resistance.