Vaccines alter the immune landscape experienced by pathogens, and hence their evolution, by targeting subsets of strains in a population, reducing the number of fully susceptible individuals, and creating or expanding classes of semi-immune hosts. The great success of vaccination against the acute childhood occurred without being undermined by pathogen evolution, but those diseases were easy targets: natural immunity was evolution-proof; all vaccination needed to do was to induce something very similar. Pathogens now under assault by vaccination are different: their natural infections induce leaky, often strain-specific immunity that usually wanes. Vaccines against these diseases will induce immunity to which natural selection has already found solutions. Evolutionary analysis is particularly warranted where vaccines are leaky, target subsets of strains or virulence determinants, involve novel technologies, or relax selection against virulence. Vaccination has been a great benefit. Continuing past successes requires evolutionary considerations at all stages of vaccine design and implementation.