Cytokines and related signaling molecules lead to profound regulatory changes in differentiated cell function, modulating immune functions, the stress response, energy metabolism, growth, and reproduction. A network of intracellular molecules that dampen or inhibit the effects of these pleiotropic factors provides a crucial counterbalance to cytokine signals. Recent studies have shown that negative feedback, initiated in the various target tissues by the cytokines themselves, is central to endocrine homeostasis. Cytokine-mediated adrenocorticotropin hormone (ACTH) and cortisol overproduction, for instance, is prevented by tightly regulated cytokine-induced intracellular negative control systems. Likewise, growth hormone (GH) signaling is abrogated by cytokine-induced proteins, providing an explanation for GH resistance and stunted growth observed in states of elevated cytokine activity, including inflammation, starvation, and chronic illness. This article explores the role of the signal suppressor SOCS-3 in inhibiting the actions of neuro-endocrine cytokines and hormones, while maintaining the plasticity of the ultimate neuro-immune endocrine responses.