Streptococcus pneumoniae is a well-known agent of community-acquired infections such as sinusitis, otitis media, pneumonia, bacterial meningitis, bacteremia and acute exacerbations of chronic bronchitis. However, the role of S. pneumoniae as a cause of nosocomial infections of respiratory tract, bloodstream and central nervous system is more and more recognized, primarily in high-risk patients with depression of their immune function. Therapy of pneumococcal infections is made difficult by the emergence and spread of bacterial resistance to penicillin and other β-lactams as well as to a number of antimicrobials such as macrolides, chloramphenicol, tetracyclines and sulfonamides. This epidemiological situation is a cause for concern world-wide, but it primarily affects some European countries, North America, South Africa and the Far East. The main consequence on therapeutic grounds is that in severe infections such as bacterial meningitis, the addition of vancomycin to a third-generation cephalosporin is advisable while awaiting laboratory test results, even in areas with low prevalence of penicillin-resistant pneumococci. However, a β-lactam agent can also be a valid choice in the presence of potentially lethal infections such as pneumonia or in the case of penicillin intermediately resistant isolates. In recent years, new alternative molecules have been introduced into clinical practice for therapy of infections caused by penicillin-resistant pneumococci. In both in vivo and in vitro studies, drugs of the classes of fluoroquinolones (levofloxacin, moxifloxacin, gatifloxacin), streptogramins (quinupristin/dalfopristin) and oxazolidinones (linezolid) have shown good microbiologic and clinical efficacy against penicillin-resistant pneumococci. In this era of world-wide spread of penicillin-resistant pneumococci, use of polysaccaride or conjugated vaccines is highly recommended.