Social relationships are a fundamental aspect of life, affecting social, psychological, physiological, and behavioral functions. While positive social interactions can attenuate stress and promote health, the social environment can also be a major source of stress when it includes social disruption, confrontation, isolation, or neglect. Social stress can impair the basal function and stress-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis, impairing function of multiple biological systems and posing a risk to mental and physical health. In contrast, social support can ameliorate stress-induced physiological and immunological deficits, reducing the risk of subsequent psychological distress and improving an individual's overall well-being. For better clinical treatment of these physiological and mental pathologies, it is necessary to understand the regulatory mechanisms of stress-induced pathologies as well as determine the underlying biological mechanisms that regulate social buffering of the stress system. A number of ethologically relevant animal models of social stress and species that form strong adult social bonds have been utilized to study the etiology, treatment, and prevention of stress-related disorders. While undoubtedly a number of biological pathways contribute to the social buffering of the stress response, the convergence of evidence denotes the regulatory effects of oxytocin in facilitating social bond-promoting behaviors and their effect on the stress response. Thus, oxytocin may be perceived as a common regulatory element of the social environment, stress response, and stress-induced risks on mental and physical health. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.