Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, meningitis, and bacteremia in children and adults. Invasive pneumococcal disease (IPD) primarily affects young children, older adults (> 65 years of age), and individuals with comorbidities or impaired immune systems. Case fatality rates range from 10 to 30% in adults with IPD but are much lower (< 3%) in children. In this article, we describe the epidemiology of IPD, risk factors, and the influence of host-and organism-specific factors on outcomes. Most cases of IPD are caused by a limited number of serotypes that vary in infectivity and virulence. Vaccinating adults and high-risk patients with the pneumococcal polysaccharide vaccine reduces the incidence of IPD in populations at risk but does not affect nasopharyngeal colonization and has had limited benefit in the population at large. Use of the heptavalent pneumococcal conjugate vaccine (PCV7) in children in the United States since 2000 has resulted in a substantial decline of IPD in both children and adults (by herd immunity), but has facilitated the emergence of serotypes not encompassed in the PCV7 vaccine. Recent reports of “replacement” serotypes that have heightened virulence are worrisome. In this chapter, we discuss the role of vaccines (both polysaccharide and conjugate) and other preventive strategies to limit this important and potentially lethal disease.