Associations between personality and health and longevity are increasingly well documented, but the causal inter-connections are often much more complex than originally anticipated. Multiple causal pathways may operate simultaneously as the individual travels an idiosyncratic route across the life-span. Therefore, a straightforward model of personality, immunity, and disease may never be established and validated, because it overlooks other key elements of the causal processes. Psychoneuroimmunology research may profit from closer integration into the broader conceptual understandings of personality and health, using a new life-span epidemiological personality approach.