This chapter deals with the capacity of the immune system to sense the intrusion of external challenges and modifications of self-components, and to provide information to the brain about these disturbances. These properties allow us to classify the immune system as a classical sensory organ. Besides its intrinsic function directed at the elimination of dangerous stimuli, the activation of the immune system also affects the functioning of other homeostatic systems, such as the endocrine and the nervous systems. We also discuss our view of how immune-derived information could be processed by the brain and integrated with other inputs that it permanently receives, leading to a resetting of regulatory adaptive systems. Due to the high energetic cost of immunity, we discuss how brain-borne cytokines, in particular IL-1, could affect glucose homeostasis. Deregulation of these immune-neuroendocrine interactions can affect brain mechanisms that include behavior, cognition, mood, and personality.