Antibiotic-resistant Streptococcus pneumoniae, particularly penicillin-resistant strains, are being identified with increasing frequency. Pneumococci with intermediate penicillin resistance (IPR) have been recovered from patients for 15 years. These strains have minimal inhibitory concentrations (MICs) for penicillin of 0.1-1.0 microgram/ml, an MIC that is 10-100 times greater than that for susceptible strains. However, in the past three years, resistant strains have been isolated that have MICs for penicillin of 2-10 microgram/ml. Disease caused by IPR strains may respond to high-dosage parenteral penicillin, but disease caused by more resistant strains, especially meningitis, requires therapy with alternative agents. Pneumococci resistant to tetracycline, sulfonamides, erythromycin, lincomycin, chloramphenicol, clinadmycin streptomycin, and rifampin have also been reported. Particularly ominous has been the development in South Africa of multiply resistant pneumococci, resistant to all the above agents, including all beta-lactam antimicrobial agents. This paper reviews the following aspects of resistant pneumococci: (1) the definitions of resistance and methods of susceptibility testing, (2) the geographic distribution of resistant strains, (3) the epidemiologic characteristics of infected patients, (4) the clinical manifestations of disease and response to therapy, (5) the distribution of serotypes and implications for use of the pneumococcal vaccine, and (6) the methods used to limit spread of resistant strains and to prevent disease. These new issues may alter the impression that pneumococcal disease is readily treated and no longer a major public health threat.