Viruses are directly or indirectly implicated in multiple sclerosis (MS). Here, we review the evidence on the virus-related pathophysiology of MS, introduce common experimental models, and explore the ways in which viruses cause demyelination. By emphasizing knowledge gaps, we highlight future research directions for effective MS diagnostics and therapies: (i) identifying biomarkers for at-risk individuals, (ii) searching for direct evidence of specific causative viruses, (iii) establishing the contribution of host genetic factors and viruses, and (iv) investigating the contribution of immune regulation at extra-CNS sites. Research in these areas is likely to be facilitated by the application of high-throughput technologies, the development of systems-based bioinformatic approaches, careful selection of experimental models, and the acquisition of high-quality clinical material for tissue-based research.