Streptococcus pneumoniae remains a major cause of infection in both children and adults, annually resulting in significant morbidity and mortality. The past two decades have seen an alarming worldwide increase in the incidence of drug-resistant S. pneumoniae (DRSP). DRSP is now common throughout the United States, and physicians are questioning how best to approach this epidemic. With the introduction of a number of newer antimicrobial agents, the potential for improved preventive measures, and a better understanding of DRSP, the approach to the management of DRSP infections may change greatly in the next few years. In this article we will review the development of DRSP, identify populations at increased risk of exposure to DRSP, address what approaches might be used to limit its spread, and suggest initial empirical therapy when treating patients with pneumonia due to DRSP.