Proinflammatory cytokine interleukin-1 (IL-1) produced during psychological and immunological stress, plays a significant role in the neuroendocrine and stress responses. Brain IL-1 is an important mediator in stress-induced stimulation of the limbic-hypothalamic-pituitary-adrenal axis and secretion of ACTH and corticosterone. This review aims to describe some signaling pathways between the limbic-hypothalamic-pituitary structures during prolonged stress responses including their sensitization and adaptation. Interleukin-1 represents an important central component operating in neurochemical and immune network for efficient coping in preventing stress-associated psycho- and neuropathology.