Wildlife vaccination is of urgent interest to reduce disease-induced extinction and zoonotic spillover events. However, several challenges complicate its application to wildlife. For example, vaccines rarely provide perfect immunity. While some protection may seem better than none, imperfect vaccination can present epidemiological, ecological, and evolutionary challenges. While anti-infection and antitransmission vaccines reduce parasite transmission, antidisease vaccines may undermine herd immunity, select for increased virulence, or promote spillover. These imperfections interact with ecological and logistical constraints that are magnified in wildlife, such as poor control and substantial trait variation within and among species. Ultimately, we recommend approaches such as trait-based vaccination, modeling tools, and methods to assess community-and ecosystem-level vaccine safety to address these concerns and bolster wildlife vaccination campaigns. The Potential of Wildlife Vaccines Highlights Vaccines vary in their efficacy and can be categorized as conferring waning, binary, or partial immunity. Some imperfect vaccines may indirectly increase parasite transmission or virulence. Target vaccine coverage depends on wildlife disease control objectives, for example, spillover prevention or conservation.