Streptococcus pneumoniae, or pneumococcus, is a common and virulent pathogen that causes a high burden of clinical disease. All demographic groups are affected; however, older adults and the immunosuppressed are at higher risk for infection of normally sterile body spaces, called invasive pneumococcal disease. Vaccination, both with free-polysaccharide and more recently conjugate protein formulations, has led to reductions in invasive pneumococcal disease. These reductions are not uniform, however, as patients with comorbid illness derive less protection from the free-polysaccharide vaccine. At best, the free-polysaccharide vaccine appears only modestly effective in protecting against nonbacteremic pneumococcal pneumonia. Conjugated protein vaccines stimulate a more vigorous immune response in young children and most adults, as measured by opsonophagocytosis assays. This suggests the conjugate vaccine may offer improved immune protection against both invasive disease and pneumonia; however, large randomized trials with clinical end points are still needed. If proven to be protective, replacement of the current free polysaccharide with conjugate vaccines would likely be cost-effective among adults over 65 years of age and those at higher risk.