Increasingly, Streptococcus pneumoniae with reduced susceptibility to penicillin is becoming a healthcare concern, not only because of the high prevalence of infections caused by this pathogen but also because of the rate at which resistance has progressed. The incidence of penicillin resistance in strains of S. pneumoniae approaches 40% in some areas of the United States, and the incidence of high-level resistance has increased by 60-fold during the past 10 years. With the exception of meningitis and otitis media, there is no conclusive evidence that the acquisition of resistance by S. pneumoniae to β-lactam antibiotics incurs greater morbidity and mortality in infections caused by this pathogen. However, if the current trends of resistance patterns continue, one can expect the morbidity and mortality to increase. The mechanism of β-lactam resistance of S. pneumoniae involves genetic mutations which alter penicillin-binding protein structure, resulting in a decreased affinity for all β-lactam antibiotics. In the treatment of infections caused by S. pneumoniae, it should not be assumed that nonsusceptibility to β-lactam antibiotics correlates with clinical ineffectiveness of these agents. On the contrary, the recommended therapy for nonmeningeal pneumococcal infections (e.g., pneumonia, sepsis, acute otitis media) includes a β-lactam antibiotic: penicillin G, amoxicillin, amoxicillin/clavulanate, cefuroxime, cefotaxime, or ceftriaxone. Recommended therapy for meningitis is cefotaxime or ceftriaxone, with the addition of vancomycin until susceptibility is known. These agents are recommended because of their ability to achieve serum/tissue concentrations greater than the minimum inhibitory concentrations (MICs) of these agents against penicillin-susceptible, penicillin-intermediate, and most penicillin-resistant strains (e.g., penicillin G, cefotaxime, ceftriaxone, amoxicillin, amoxicillin/clavulanate, and cefuroxime), or their ability to provide adequate concentrations in cerebrospinal fluid (e.g., cefotaxime, ceftriaxone).