Multiple sclerosis (MS) is widely recognized as a progressive, inflammatory neurogenerative disease, for which the causative agent(s) or triggers are not well known. A recent hypothesis is that MS is caused, at least to some extent, by chronic venous insufficiency of the extracranial venous drainage. In this chapter, we explore the historical and modern perspectives on possible vascular etiologies to multiple sclerosis, parallels from other cerebrovascular diseases, and identify future areas of exploration.