Since the first vaccine was invented in the late eighteenth century, vaccines revolutionized biomedical approaches to infectious disease prevention and saved hundreds of millions of lives from smallpox, influenza, measles, whooping cough, and Covid-19. Despite the undeniable success of this medical technology, vaccines have always given some people pause, and others have steadfastly rejected vaccinations for themselves and their children. Although historians and social scientists have explained many causes of vaccine hesitancy in the United States, this dissertation is the first analysis of vaccine hesitancy that treats it as a part of United States religious history. Covering three hundred years of vaccine history, this dissertation charts and analyzes the religious concepts and bodily practices that informed increasing vaccine skepticism over four different historical periods, culminating in the Covid-19 era. It explains how vaccine skeptics crafted their arguments, worldviews, and bodily practices and why their skepticism was often subtly religious. Vaccine skeptics routinely placed religious ideas––purity vs. pollution, sacralized motherhood and childhood, divine sovereignty, and moral individualism––at the center of their arguments against vaccines. To protect bodily sovereignty and purity, they enacted rituals to stave off corruption. These rituals included self-education, holistic healing, intensive mothering, and detoxing bodies and environments. In different eras, skeptics created moral communities that coalesced behind shared values about bodies, health, and wellness. They negotiated the limits of bodily and medical authority, the responsibility of the individual to the collective, and the connection between the worldly physical body and the transcendent soul. Skeptics perceived the standardizations required of biomedicine and public health as immoral, so they agitated against state-mandated vaccinations. Their moral communities were prevalent on both the Left and the Right of the religious and political spectrums in the United States. From the debates over smallpox inoculations in colonial Boston to the furor over Covid-19, they have found common ground where few other movements have.