Communication between the central nervous and immune systems lies at the heart of the neuroimmune axis. We trace here some of the major conceptual hurdles which were raised, first against the acceptance of a neuroimmune axis and later in understanding it. We review the major concepts formulated and established during the last two decades and focus on four pathways that have been proposed as important in communication: the neural route, circumventricular organs, blood-brain barrier transport of cytokines, and secretions from BBB cells. These and other pathways have established the existence of a neuroimmune axis, but raise new questions on how they act and interact with one another.