Biomedicine, the predominant medical model that emerged during the twentieth century, is founded conceptually on mechanism and reductionism, especially in terms of portraying the patient as a machine reducible to its component parts. Systems medicine, in contrast, has emerged during the early part of the twenty-first century to address problems arising from biomedicine’s failure to cure diseases such as cancer. In this paper, a conceptual framework is provided for shifting from mechanistic biomedicine to organismal systems medicine. Specifically, organicism and holism provide the necessary foundation for viewing the patient not simply as a diseased or dysfunctional body part but as a whole person embedded within a biological, psychological, social, and environmental framework. Although biomedicine’s approach has identified many of the physiological and pathological components of health and disease, a shift to organismal systems medicine promises to deliver the principles and rules by which these components relate and interact with one another in a holistic rather than simply in a reductive mechanistic fashion.