Etanercept is a potent antagonist of TNF, a pleotropic immune signaling molecule that is also a pivotal regulator of synaptic function. Excess TNF is centrally involved in the pathogenesis of a variety of inflammatory neurological disorders, including Alzheimer’s disease, sciatica, traumatic brain injury and spinal cord injury. Perispinal etanercept produces rapid improvement in both Alzheimer’s disease and sciatica and in other forms of disc-related pain. Basic research and the observed clinical effects suggest that etanercept has the surprising ability to penetrate into the cerebrospinal fluid after perispinal administration. Perispinal administration is a novel method of delivery designed to introduce this anti-TNF molecule into the bidirectional cerebrospinal venous system and the cerebrospinal fluid to facilitate its selective delivery to either spinal structures or the brain. The scientific rationale, physiologic mechanisms, clinical effects and potential clinical indications of this therapeutic approach are the subject of this article.