The brain is the central organ of responding to stress and is vulnerable but resilient; it communicates reciprocally with the rest of the body. This Viewpoint explains the concepts of allostasis and allostatic loads as they epigenetically affect neural and systemic processes over the lifecourse. These concepts reveal how the brain and body influence each other during the course of psychiatric disorders with frequent multimorbidity,^1–3 a point that needs more acknowledgement in the Research Domain Criteria matrix.