Much attention has been paid to the potential role of the immune system in the pathophysiology of major depression in humans. While activation of innate immune responses currently dominates the research landscape, early studies in depressed patients demonstrating impairment in acquired immune responses, in particular T cell responses, may warrant further consideration. Intriguing data suggest that activated T cells may play an important neuroprotective role in the context of both stress and inflammation. For example, generation of autoreactive T cells through immunization with central nervous system (CNS) specific antigens has been shown to reverse stress-induced decreases in hippocampal neurogenesis as well as depressive-like behavior in rodents. In addition, trafficking of T cells to the brain following stress, in part related to glucocorticoids, has been found to reduce stress-induced anxiety-like behavior. Data indicate that T regulatory cells may also play a role in depression through downregulation of chronic inflammatory responses. Based on the notion that T cells may subserve neuroprotective and anti-inflammatory functions during stress and inflammation, impaired T cell function may directly contribute to the development of depression. Indeed, increased sensitivity to apoptosis as well as reduced responsiveness to glucocorticoids, may not only decrease the availability of T cells in depressed patients, but also may reduce their capacity to traffic to the brain in response to relevant neuroendocrine or immune stimuli. Further elucidation of T cell pathology may lead to new insights into immune system contributions to depression. Moreover, enhancement of T cell function may represent an alternative strategy to treat depression.