The first animal-to-human blood transfusions performed in seventeenth-century England focused on patients suffering from mental diseases such as melancholy. Many physicians diagnosed melancholy as a disease of the body, mind, and soul in which blood played a key role. Philosophy, religion, and folklore helped formulate blood as an elusive yet powerful substance with access to immaterial mind and soul in addition to the body. English physician Richard Lower conducted these first transfusions yet recorded little about his personal theories regarding how melancholy and blood affected the body, mind, and soul. The philosophies of Lower’s colleagues, Thomas Willis and Robert Boyle, provide a new context and reasoning behind Lower’s experiments. Lower, Willis and Boyle’s combined work explains the theory of blood diseases and how blood transfusions could potentially treat mental diseases including melancholy.