Ecological Immunology assumes that immunologicaldefenses must be minimized in terms of cost (energyexpenditure). To reach this goal, a complex and stilllargely unexplored strategy has evolved to assuresurvival. From invertebrates to vertebrates, an integratedimmune–neuroendocrine response appears to be crucialfor the hierarchical redistribution of resources within thebody according to the specific ecological demands.Thus, on the basis of experimental data on the intimaterelationship between stress and immune responses thathas been maintained during evolution, we argue that abroader perspective based on the integration of immuneand neuroendocrine responses should be adopted todescribe the comprehensive strategy that the bodyutilizes to adapt to dynamic environmental conditions.We discuss the hypothesis that a bow-tie architecturemight be suitable to describe the variety of immune–neuroendocrine inputs that continuously target cells andorgans while, at the same time, fulfilling the basicrequirement of minimizing the cost of immune–neuroendocrineresponses. Bow-tie architectures are able toconvert a variety of stimuli (fan in) into a wide range offine-tuned responses (fan out) by passing through theintegrating activity of a core (knot) constituted by alimited number of elements. Finally, we argue thatthe ecologically negotiated immune–neuroendocrinestrategies may have deleterious effects in the postreproductiveperiod of life when, at least in humans, chronic, low-grade, systemic inflammation develops, in accordance with the antagonistic pleiotropy theory of aging.