Changes in the blood-brain barrier (BBB) are crucial to the pathogenesis of multiple sclerosis (MS). There are currently few established treatments for MS, and interferon-beta (IFN-beta) therapy is one of the most promising - proposed to act as an immunomodulator of the cytokine network reducing inflammatory damage. However, there is increasing evidence that direct effects on the BBB could also be relevant. This review surveys the evidence that IFN-beta stabilizes the BBB, and that this process itself might be the key target. Understanding IFN-beta-derived changes at the BBB will not only provide new insights in the pathogenesis of MS but will also be helpful to develop new, more-specific drugs for MS treatment.