Pneumococcal infection remains a common cause of serious morbidity and mortality throughout the world. Until recently, clinical isolates of pneumococci that were penicillin resistant were rare. However, 4% to 5% of the clinical isolates in the United States were recently found to be either intermediately resistant or highly resistant to penicillin. Clinicians in every field of medicine must therefore be better informed regarding penicillin-resistant pneumococcal infections to minimize their attendant morbidity and mortality and increase compliance with preventive measures. We reviewed the molecular, genetic, and epidemiologic aspects of penicillin-resistant pneumococcal infections, with emphasis on their microbiologic and clinical features.