Drug-resistant strains of Streptococcus pneumoniae have now been reported from all continents and have become the predominant pathogens in some areas; many strains are resistant to multiple agents. Because of the importance of pneumococci in the etiology of meningitis, the criteria used to assess susceptibility are conservative: strains with minimal inhibitory concentrations (MICs) of penicillin G of less than or equal to 0.06 microgram/mL are regarded as susceptible, those with MICs of 0.1-1 microgram/mL are considered intermediately resistant, and those with MICs of greater than 1 microgram/mL are designated highly resistant. The diagnosis, treatment, and prevention of infections due to resistant pneumococci are the subjects of this review. Methods of susceptibility testing have now been well defined for pneumococci. Screening for penicillin resistance with 1-microgram oxacillin disks is recommended for all clinically significant isolates. The activity of other beta-lactam agents against penicillin-resistant strains has been documented, and the MICs of a number of non-beta-lactam agents have been determined as well. Treatment of resistant pneumococcal infections depends on the site of infection, the degree of resistance to penicillin G, the resistance of the infecting strain to other agents, the severity of disease, the presence of underlying conditions, and the dose and route of administration of antimicrobial agents. Current recommendations for treatment are based on retrospective case studies, and adequate prospective studies providing more definitive data are needed. Prevention of pneumococcal infections in children less than 2 years of age and in the elderly remains a problem. Improved vaccines must be developed for this purpose.