Social isolation predicts morbidity and mortality from cancer, cardiovascular disease, and a host of other causes. The mechanisms by which the social world impacts on health are poorly understood, in part because of lack of specificity in the conceptualization and operationalization of relevant aspects of social relationships and physiological processes. Perceived social isolation, commonly termed loneliness, may represent a link between the epidemiological and biological levels of analysis. Research is presented that investigates loneliness as a social factor of importance in three predisease pathways: health behaviors, excessive stress reactivity, and inadequate or inefficient physiological repair and maintenance processes. Empirical evidence of autonomic, endocrine, and immune functioning suggests that the physiological effects of loneliness unfold over a relatively long time period. For cancer patients, interventions should be aimed at providing instrumental support for the immediate demands of the disease.