The communication between the brain, immune and vascular systems is a key contributor to the onset and progression of neurological diseases. Our research has dissected the cellular and molecular interface blood proteins utilize to interact with nervous system cells. We uncovered pleiotropic roles for the blood coagulation factor fibrin in neuroinflammation, neurodegeneration, and inhibition of repair in a wide range of neurological diseases. A first-in-class fibrin-targeting immunotherapy we designed to selectively block neurotoxic inflammation without adverse effects on hemostasis has now advanced in Phase 1b clinical trials for Alzheimer’s disease and ophthalmic diseases. The blood-brain-immune interface can be harnessed for pioneering discoveries and therapeutics for neurological diseases.