A conceptual obstacle for understanding immune-to-brain signaling is the issue of the blood–brain barrier (BBB). In the last 30years, several pathways have been investigated to address the question of how peripheral immune signals are transmitted into the brain. These pathways can be categorized into two types: BBB-dependent pathways and BBB-independent pathways. BBB-dependent pathways involve the BBB as a relay station or porous barrier, whereas BBB-independent pathways use neuronal routes that bypass the BBB. Recently, a complete BBB-dependent ascending pathway for immune-to-brain signaling has been described. Details of BBB-independent pathways are still under construction. In this review, I will summarize the current progress in unraveling immune-to-brain signaling pathways. In addition, I will provide a critical analysis of the literature to point to areas where our knowledge of the immunological afferent signaling to the central nervous system is still sorely lacking.