Streptococcus pneumoniae remains the most common bacterial cause of community-acquired pneumonia, and these infections are associated with significant morbidity and mortality worldwide. A major concern is the increasing incidence of antibiotic resistance among pneumococcal isolates, which, in the case of certain of the antibiotic classes, has been associated with treatment failure. Yet despite multiple reports of infections with penicillin-resistant pneumococcal isolates, no cases of bacteriologic failure have been documented with the use of penicillin or ampicillin in the treatment of pneumonia caused by penicillin-resistant pneumococci. Current prevalence and levels of penicillin resistance among pneumococal isolates in most areas of the world do not indicate a need for substantial treatment changes with regard to the use of the penicillins. For infections with penicillin-sensitive strains, penicillin or an aminopenicillin in a standard dosage will still be effective for treatment. In the cases of strains with intermediate resistance, beta-lactam agents are still considered appropriate treatment, although higher dosages are recommended. Infections with isolates of high-level penicillin resistance should be treated with alternative agents such as the third-generation cephalosporins or the new antipneumococcal fluoroquinolones. In the case of the cephalosporins, pharmacodynamic/pharmacokinetic parameters help predict which of those agents are likely to be successful, and the less active agents should not be used. Debate continues in the literature with regard to the impact of macrolide resistance on the outcome of pneumococcal pneumonia, with some investigators providing evidence of an "in vivo-in vitro paradox," referring to discordance between reported in vitro resistance and clinical success of macrolides/azalide in vivo. However, several cases of macrolide/azalide treatment failure have been documented, and many clinicians recommend that these agents not be used on their own in areas with a high prevalence and levels of macrolide/azalide resistance. However, evidence is emerging to show beneficial effects on outcome with combination therapy, especially that of a beta-lactam agent and a macrolide given together to sicker, hospitalized patients with pneumococcal pneumonia. In an attempt to prevent the emergence of resistance, it has been recommended by some that the new fluoroquinolones not be used routinely as first-line agents in the treatment of community-acquired pneumonia; instead, they say, these agents should be reserved for patients who are allergic to the commonly used beta-lactam agents, for infections known to be or suspected of being caused by highly resistant strains, and for patients in whom initial therapy has failed.