The prevalence of drug-resistant Streptococcus pneumoniae (DRSP) has increased worldwide. Although unfavorable outcomes in meningitis due to DRSP have been well-described, the clinical impact of DRSP on other manifestations of pneumococcal infection warrants further study. Empiric combination vancomycin and extended-spectrum cephalosporin (cefotaxime or ceftriaxone) therapy is indicated for the following clinical indications: purulent meningitis, life-threatening pneumonia, and suspected sepsis in patients predisposed to invasive pneumococcal disease, for example, sickle cell disease, HIV infection, and nephrotic syndrome. In addition to clinical management issues, other implications of the emergence of DRSP include identification of resistant strains, local and national surveillance, and prevention. Preventive measures include judicious antibiotic use, appropriate use of the currently available 23-valent pneumococcal vaccine, and development and implementation of a protein-conjugate vaccine.