The immune system and the hypothalamic-pituitary (H-P) axis are functionally connected, so that exposure to antigens elicits a coordinated response which allows the organism to successfully withstand immunologic challenges. An important feature of this bilateral communication is the appearance of proteins released into the circulation by activated immune cells. These proteins, called cytokines or interleukins, stimulate the activity of the H-P axis, thus increasing circulating ACTH and corticosteroid levels. This in turn induces metabolic changes such as increases in energy substrates, restrains the activity of specific immune cells, and alters the release of secretagogues important for both the immune system and neuroendocrine organs. After acute increases in blood-borne levels of cytokines, nerve terminals in the median eminence, particularly those containing corticotropin-releasing factor (CRF), represent an important site of action of these immune signals. Subsequently, changes take place within the brain in general and the hypothalamus in particular. They include the synthesis/release of peptides such as CRF and vasopressin, of neurotransmitters such as catecholamines and prostaglandins, and of cytokines themselves. Upon prolonged exposure to blood-borne immune signals additional mechanisms come into play, including those taking place directly at the pituitary level. These observations indicate that cytokines released into the general circulation act on multiple sites within the H-P axis, a phenomenon that relies on the recruitment of a large number of pathways. This review discusses these pathways and the mechanisms through which they allow cytokines to convey the occurrence of immune activation to the brain.