Like any biotechnology innovation, the production of human vaccines in plants will succeed partly on its technical merits, and partly on the social acceptance of the new technology. The latter is harder to predict than the former, and may pose the most significant challenges to plant-derived vaccines’ (PDVs) success. To realize the potential benefits of plant-derived vaccines, especially for developing countries in which health inequities are most acute, social challenges must be anticipated and addressed in a way that will foster concrete policy alternatives. The ultimate aim is to minimize the risk of premature social rejection of plant-derived vaccines.