Penicillin resistance among strains of Streptococcus pneumoniae has emerged as an important worldwide problem. Beta-lactam-resistant pneumococci also can be resistant to erythromycin, trimethoprim/sulfamethoxazole and tetracycline and are uniformly susceptible to vancomycin and imipenem. Crowded conditions (e.g. daycare centers, hospitals, military barracks and prisons) and prior beta-lactam antibiotic therapy are the principal predisposing factors to colonization and disease. To date the two conditions caused by penicillin- and cephalosporin-resistant pneumococci that have been especially difficult to treat are acute otitis media and meningitis. Concentrations of beta-lactams in cerebrospinal fluid and middle ear fluid are usually inadequate to achieve prompt eradication of some intermediately resistant and most highly resistant pneumococcal strains. Use of unconventional therapeutic agents such as ceftriaxone or clindamycin for acute otitis media and vancomycin or rifampin for meningitis may be necessary. Control of this global problem will require innovative methods to reduce the selective pressure that results from widespread antibiotic use and to develop effective pneumococcal vaccines that are immunogenic in young infants.