Communication is central to all patient encounters. Palliative care clinicians receive and provide education about communication content and processes. The mechanisms underlying communication, such as individual neurobiology, psychological heuristics, and moral grounding, are rarely included in this education. Information about those communication mechanisms is fragmented across several disciplines, and though much has been learned in recent years, is incomplete. Interdisciplinary biopsychosocial care is a widely accepted conceptual framework for high quality, patient-centered clinical practice. A novel biopsychosocial communication framework can give palliative care clinicians an organized way to conceptualize the mechanisms underlying commonly used communication content and processes. Such a framework may improve patient-centered clinical practice, clinician education, and clinical communication research. This novel biopsychosocial communication framework postulates that learnable communication procedures and techniques are clinically effective in diverse patient populations and scenarios because human beings share similar underlying communication mechanisms. These mechanisms are founded in a common neurobiology, psychology and sociocultural context. The utility in adoption of a biopsychosocial communication framework can be compared to recent developments in cancer treatment. Historical chemotherapy’s “shotgun” approach has been replaced by targeted gene-specific therapy based on an understanding of the genetic mechanisms of oncologic diseases. A biopsychosocial communication framework enables clinicians to replace the current “shotgun” approach to communication through application of targeted, “patient-centered communication” procedures based on understanding of the mechanisms underlying communication. To highlight the efficacy of this framework, the authors present the case of PR, an eight month old boy with severe acute necrotizing encephalitis of the brainstem following viral infection. The authors employed targeted communication procedures to 1. Build trust with the family utilizing recognized neurobiological processes, 2. Elicit family goals, values and expectations utilizing psychological heuristics, and 3. Provide medical recommendations framed in concordance with the family’s sociocultural and spiritual worldview. The family expressed that the palliative care team recommendations respected their family values, their moral responsibilities both as parents and members of their spiritual community, and simultaneously recognized the unfortunate biological pathology that afflicted their son. The family elected to extubate PR and provide comfort care in the ICU, with legacy building activities including time and conversation with school-aged siblings, hand prints, foot molds and family photographs. PR died peacefully and surrounded by family approximately 24 hours after extubation. A biopsychosocial communication framework will improve the future practice of palliative care in at least three specific ways. First, improved conceptual organization of communication mechanisms will enable providers to develop novel, empathic, and more individualized patient-centered communication procedures. Second, it will organize and inform the education of clinicians about communication content and processes. Third, it will contribute to the interdisciplinary understanding of human communication through clinical communication research.