Social interactions have long-term physiological, psychological, and behavioral consequences. Social isolation is a well-recognized but little understood risk factor and prognostic marker of disease; it can have profoundly detrimental effects on both mental and physical well-being, particularly during states of compromised health. In contrast, the health benefits associated with social support (both reduced risk and improved recovery) are evident in a variety of illnesses and injury states; however, the mechanisms by which social interactions influence disease pathogenesis remain largely unidentified. The substantial health impact of the psychosocial environment can occur independently of traditional disease risk factors and is not accounted for solely by peer-encouraged development of health behaviors. Instead, social interactions are capable of altering shared pathophysiological mechanisms of multiple disease states in distinct measurable ways. Converging evidence from animal models of injury and disease recapitulates the physiological benefits of affiliative social interactions and establishes several endogenous mechanisms (inflammatory signals, glucocorticoids, and oxytocin) by which social interactions influence health outcomes. Taken together, both clinical and animal research are undoubtedly necessary to develop a complete mechanistic understanding of social influences on health.