Viral infections may have an important role in the precipitation or relapse of multiple sclerosis (MS) and its treatment. This review describes the normal immune response to viral infection, the possible associations between viral infections and MS therapy, and the impact of sphingosine 1-phosphate (S1P) receptor (S1PR) modulation with fingolimod (FTY720) on the immune responses to viral infection. The physiologic immune response to viral infection involves lymphocyte activation and control of the circulation of subsets of lymphocytes with different functions between the lymph nodes, vascular system, and tissues, under the control of the S1P/S1PR signaling mechanism. In MS, it has been postulated that viral infections may play a role in triggering MS relapses, with virus-specific T cells being responsible for the demyelinating lesions within the CNS. Fingolimod-an S1PR modulator approved for the treatment of relapsing MS in some countries-is thought to act by downmodulating lymphatic S1P subtype 1 receptors. This retains naïve T cells and central memory T cells, but not effector memory T cells, within the lymph nodes and prevents their circulation to the CNS. Evidence from infection models supports that the selective effects of fingolimod on T cell subsets allows key immune responses to be preserved during therapy. However, in patients, long-term observation is important as both the risk of cancer and infection is potentially increased by the use of any immunomodulatory agent.