There is evidence suggesting that immunosenescence can be accelerated by external factors such as chronic stress. Here we review potential psychoneuroendocrine determinants of premature aging of the immune system and discuss available interventions aimed at attenuating immunosenescence. Chronic stress may accelerate various features of immunosenescence by activating key allostatic systems, notably the hypothalamic-pituitary-adrenal axis. The immunological impact of such neuroendocrine dysregulation may be further amplified by a dramatic decline in dehydroepiandrosterone (DHEA) levels, acting in part as an endogenous glucocorticoid antagonist. Stress-buffering strategies show beneficial effects on various biomarkers in elderly populations. Likewise, supplementation of DHEA, melatonin or growth hormone has yielded significant beneficial effects in a number of studies, including: increased well-being, memory performance, bone mineral density and improved immunocompetence as evidenced by results of in vitro (T cell proliferation, cytotoxicity, cytokine production), and in vivo immune challenges. However, the side-effects of hormonal supplementation are also discussed. Finally, moderate exercise via the promotion of cortisol/DHEA balance or epigenetic modifications, is associated with lower serum pro-inflammatory cytokines, greater lymphoproliferative responses and lower counts of senescent T cells. Taken together, these data suggest that immune system is plastic and immunosenescence can be attenuated psychoneuroendocrine interventions.