This paper introduces Tibetan pill traditions and examines two exceptional pill formulas that emerged from an early Buddhist–medical interface in Tibet, but followed different trajectories due to the increased specialization of religious and medical knowledge. “Black pills” are the most revered consecrated healing compound of the Karmapas (the incarnate heads of the Karma Kagyü School of Tibetan Buddhism), while the “Cold Compound Black Pill”—a precious pill known as Rinchen Drangjor—is one of Tibetan medicine’s most complex formulas still produced today. Based on both textual research and ethnographic fieldwork in India, I critically explore the principal factors that link these black pill traditions. I argue that parallels in the use of potent substances and their processing offer examples of how strongly entangled medical and religious approaches are with respect to healing practices that include blessings, protection, spiritual support, and medical treatment. My findings reveal that although there are distinct areas of medical and religious specialized practices in the black pill traditions, consecrated multi-compounds are added to both types of black pills to enhance potency and ensure the continuation of lineage affiliations to certain Buddhist schools. I also show how political and sectarian conflicts within certain Buddhist schools may affect some of these rare pill practices.