Interleukin-12 and tumor necrosis factor (TNF)-alpha promote T-helper (Th) 1 responses and cellular immunity, whereas IL-10 suppresses Th1 activities and stimulates Th2 and humoral immune responses. Recent evidence indicates that glucocorticoids, norepinephrine, epinephrine, histamine, and adenosine inhibit the production of human IL-12 and TNF-alpha, whereas they do not affect or even stimulate the production of IL-10. Through this mechanism these neuroendocrine mediators may cause a selective suppression of Th1 responses and a Th2 shift rather than generalized Th suppression. The substantial Th2-driving force of endogenous stress mediators, as well as histamine and adenosine, can be amplified to a great extent during certain conditions and may play a role in increased susceptibility of the organism to various infections that are normally cleared by Th1 responses. In addition, conditions that contribute to a substantial increase or decrease of local or systemic concentrations of these mediators via modulation of IL-12, TNF alpha/IL-10 balance may also play a role in induction, expression, and progression of certain autoimmune diseases, allergic/atopic reactions, and tumor growth. These conditions include: acute or chronic stress; cessation of chronic stress or chronic hypoactivity of the stress system; severe exercise; serious surgical procedures or traumatic injuries; major burns; severe ischemia or hypoxia; pregnancy and the postpartum period. Thus, better understanding of the neuroendocrine regulation of IL-12, TNF-alpha/IL-10 balance might help the development of new therapeutic strategies for the treatment of Th1- and Th2-mediated human diseases.