The adaptive response to physical or psychological challenges or threats involves the modulation of the three regulatory systems: the nervous, endocrine and immune systems. Correct communication between these systems is required to maintain a homeostatic balance, and to guarantee the health and survival of the individual. While the stress response is essential for survival, failure to cope with a stress can impair the function of these regulatory systems and prevent effective communication between them. Under such circumstances, the loss of homeostasis ultimately leads to the development of pathologies that can compromise survival. Social species live in groups, the maintenance of which ensures the survival of the individual by providing protection from environmental threats. However, the disruption of social bonds in such species constitutes a potent emotional stress. Thus, social isolation is considered a risk factor for morbidity and mortality. The response to isolation or loneliness can vary greatly between individuals due to the influence of many factors, some of which will be considered in this Review. These factors can exert a significant influence on the three regulatory systems throughout the lifespan of the organism, and they include characteristics of the stressor itself (e.g., duration), as well as those of the organism (e.g., biological age), in addition to external factors (e.g., environmental events).