Multiple sclerosis (MS) is a central nervous system (CNS) white-matter demyelinating disease affecting young adults. The disease has an autoimmune component, with the presence of self-reactive lymphocytes targeting myelin peptides such as myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG), leading to inflammation and myelin destruction within the brain and spinal cord. The viral hypothesis in MS is hampered by the lack of evidence for a specific agent, in addition to the weakness of the results of analytical studies that have tested the association between MS and previous infections. None of the organisms so far investigated for a role in MS has gained acceptance as the causative agent. Although several studies have implicated the role of viruses in the etiology of MS, with the temporal relationship sometimes being impressive, many of the associations appear less than convincing, and even for those that seem to be on solid footing, there is no real understanding of the underlying mechanism(s). The strict criteria of evidence based medicine that includes the detection of viral DNA/RNA in the brain or spinal cord of the patients with MS, confirmation of epidemiological studies in a variety of geographic regions, and validation of viral antibodies by several laboratories and in comparison with the normal population have not come close to be satisfying. Additional studies are needed to clarify any connection.