Blood-brain barrier (BBB) disruption, perivascular inflammation, demyelination, and axonal damage are key histopathological hallmarks of multiple sclerosis (MS). The vast majority of MS lesions develop around disrupted blood vessels. This is often attributed to active inflammation and the infiltration of immune cells into the central nervous system (CNS). Indeed, evidence of BBB disruption by gadolinium enhancement on magnetic resonance imaging (MRI) constitutes the most reliable indication of active inflammatory MS lesions. However, increasing evidence highlights a more central role for the leakage of blood factors into the CNS -an inevitable consequence of BBB disruption- whose entry precedes and promotes new lesion formation. Fibrinogen is a soluble blood protein known for its role in coagulation, through its rapid conversion to fibrin, the foundation of blood clots. Analyses in human MS tissue and in several animal models identified fibrinogen in the CNS prior to leukocyte infiltration, and the onset of demyelination, or clinical symptoms. Moreover, extensive preclinical studies demonstrated that fibrinogen is unique among other blood proteins or coagulation factors that may also enter the CNS, as it promotes inflammatory processes within perivascular lesions, and thereby contributes to neuronal damage, and inhibits tissue repair processes.