Mass vaccine hesitancy, along with outright opposition to immunization, is by no means solely an artifact of the COVID-19 era. Rather, controversies over vaccination in American history go back literally three centuries, to an intense conflict in Puritan Boston that inspired an assassination attempt on Cotton Mather. This seminar will explore this long history, focusing on three periods: the early eighteenth century, the Progressive Era, and the decades after World War II. We will especially reflect on the complex legacy of populism in all of these conflicts. Using this conceptual lens inspires us to see vaccination struggles as important episodes in the complex history of American democracy, involving issues such as civil liberties, bodily autonomy, governmental coercion, eugenics, natural medicine, conspiracy theories, and popular understandings of science. Ultimately, we can hope that a more complex history might inspire a more complex evaluation of the ways in which vaccination politics play out in the present day.