The brain is the key organ of social connections and processes, and the same objective social relationships can be experienced as caring and protective or as exploitive and isolating. We have provided evidence that the perception of social isolation (i.e. loneliness) impacts the brain and behavior and is a risk factor for morbidity and mortality. The causal role of loneliness on neural and neuroendocrine mechanisms is difficult to test conclusively in humans. Mechanistic animal studies provide a lens through which to evaluate the neurological effects of a member of a social species living chronically on the social perimeter. Experimental studies show that social isolation produces significant changes in brain structures and processes in adult social animals. These effects are not uniform across the brain or across species, but instead are most evident in brain regions that reflect differences in the functional demands of solitary versus social living for a particular species. Our current work underscores the importance of integrating human and animal research to delineate the mechanisms through which social relationships impact the brain, health, and well-being.