This first of three parts of the review examines the evidence for the involvement of the pro-inflammatory cytokine, Tumour Necrosis Factor-alpha (TNFα) in regulating normal brain activity. The second part examines changes in TNF-α implicated in several neuropathologies. Part III reviews the clinical evidence based on Part I and II for use of anti-TNF therapy to target and for treating these health problems, including chronic stroke, dementias, neuropathic pain or traumatic brain injury. All of these can become chronic illnesses and are of major incidence with a grossly unmet need to improve their treatment. The intent of the three part review is to present the overwhelming scientific and medical basis why research studies and trials to evaluate the use of the perispinally administered anti-TNFα drug, Etanercept, are justified to allow it to become a front-line standard therapy.