This article addresses the sacredness of Ayahuasca from the perspective of the global shamanic vocation. If encounters with Ayahuasca are said to revitalize forms of sacredness in contemporary societies, this is perhaps clearest in cases where individuals understand themselves to be called to lead ceremonies. Recognizing the global scale of Ayahuasca shamanism, we compare facilitators of ceremonies in two societies to discern differences and similarities in how Ayahuasca vocations exist in differently modernized societies: Peru, a predominantly Catholic society with a substantial Indigenous Amazonian population and an active Ayahuasca shamanism tourism sector, and Denmark, a secular society in Northern Europe, where Ayahuasca is illegal. Building on recent reappraisals of Weber’s reflection on vocation and Durkheim’s theory of the sacred, we argue that being called by Ayahuasca to follow shamanic vocations in contemporary societies leads to tensions around the need to both justify and resist the rationalization of Ayahuasca. Keywords: Ayahuasca, shamanism, sacredness, secularism, vocation