Studies of prolonged separation from the attachment figure that were conducted with infant monkeys during the middle of the 20th century identified a passive behavioral response, termed “despair,” that appeared to model human depressive illness. Studies in guinea pigs, which exhibit filial attachment that resembles attachment in monkeys, have described a similar passive response to briefer periods of maternal separation. Recent evidence indicates that elements of the immune system mediate the passive behavioral response of guinea pigs. These findings accord well with current ideas that immune responses contribute to depressive illness, suggest new hypotheses about how maternal separation might promote depression, and give us a rodent model in which such hypotheses might be tested.