The discovery of stenoses in the azygous and internal jugular veins, the so-called chronic cerebrospinal venous insufficiency that accompanies multiple sclerosis, has enabled the reinterpretation of knowledge about this neurologic disease. Pathologic venous outflow from the central nervous system appears to lead to two main problems. Firstly, it disassembles the blood-brain barrier and may allow the penetration of nervous parenchyma by glutamate and leukocytes. Secondly, it may result in significant hypoperfusion of the brain and spinal cord. These two overlapping pathologies are likely to trigger plaques through caspase-1-driven pyroptosis of oligodendrocytes and to evoke neurodegeneration via glutamate excitotoxicity. Moreover, brain hypoperfusion may lead to chronic fatigue and other global neurologic symptoms. It is hoped that this review will help to elucidate new strategies and treatments for multiple sclerosis and will show new avenues for the research on this debilitating disease.