The 23-valent pneumococcal polysaccharide vaccine is known to be economically reasonable in adults. With the 13-valent pneumococcal conjugate vaccine (PCV13) now available, the question is whether 23-valent pneumococcal polysaccharide vaccine offers sufficient protection in adults compared with PCV13. Our cost-effectiveness analyses favor adult PCV13 use, but results depend largely on assumptions regarding PCV13 effectiveness in preventing non-bacteremic pneumococcal pneumonia and on herd immunity effects from childhood PCV13 use, neither of which are well characterized at present. An ongoing randomized trial of adult PCV13 use and future surveillance data should clarify these issues for some population groups, but in others, such as the immunocompromised, modeling that rigorously accounts for uncertainty can and should be used to assist policymakers in their decisions.