The review compares the principles of organization of the brain and immune system, two important organs developed over 500 million years in multicellular organisms, including humans. It summarizes the latest results from research in neurosciences and immunology concerning intercellular communication. While in the brain, intercellular communication is primarily based on exchange of electrical signals, this is not the case in the immune system. The question, therefore, arises as to whether nature developed two entirely different systems of organization. It will be demonstrated that a few basic principles of brain and immune responses are organized in a different way. A majority of intercellular communications, however, such as the formation of synapses, are shown to have many similarities. Both systems are intimately interconnected to protect the body from the1 dangers of the outside and the inside world. During homeostasis, all systems are in regulatory balance. A new hypothesis states that the central systems surrounded by bone, namely the central nervous system (CNS) and the central immune system (CIS), are based on three types of stem cells and function in an open but autonomous way. T cell immune responses to antigens from blood and cerebrospinal fluid protect the system and maintain neuroimmune homeostasis. The newly discovered tunneling nanotubes and extracellular vesicles are postulated to play an important role in crosstalk with already known homeostasis regulators and help in cellular repair and the recycling of biologic material. Three examples are selected to illustrate dysfunctions of homeostasis, namely migraine, multiple sclerosis, and brain cancer. The focus on these different conditions provides deep insights into such neurological and/or immunological malfunctions. Technological advances in neurosciences and immunology can enable neuroimmunomodulation and the development of new treatment possibilities.