Immunological changes associated with aging play a major role in both the blunted responses to infections as well as to vaccines intended to prevent many of these infections. Several independent studies on immune correlates of poor vaccine responsiveness have identified a novel immune biomarker of reduced antibody response to vaccination, namely high proportions of memory CD8 T lymphocytes lacking expression of the CD28 costimulatory molecule. Research on this population of CD8⁺CD28⁻ T lymphocytes has documented characteristics suggestive of replicative senescence, including inability to proliferate, reduced telomere length, and altered cytokine profiles. CD8⁺CD28⁻ T lymphocytes have also been associated with suppressor functions and with early mortality in the elderly. This article discusses some of the challenges involved in custom-designing vaccines for the elderly, and suggests several immunomodulatory strategies that may enhance vaccine responsiveness in this age group.