Sphingosine kinase 1 (SphK1) is an enzyme that phosphorylates the lipid sphingosine to generate sphingosine-1-phosphate (S1P). S1P can act intracellularly as a signaling molecule and extracellularly as a receptor ligand. The SphK1/S1P axis has well-described roles in cell signaling, the cell death/survival decision, the production of a pro-inflammatory response, immunomodulation, and control of vascular integrity. Agents targeting the SphK1/S1P axis are being actively developed as therapeutics for cancer and immunological and inflammatory disorders. Control of cell death/survival and pro-inflammatory immune responses is central to the pathology of infectious disease, and we can capitalize on the knowledge provided by investigations of SphK1/S1P in cancer and immunology to assess its application to selected human infections. We have herein reviewed the growing literature relating viral infections to changes in SphK1 and S1P. SphK1 activity is reportedly increased following human cytomegalovirus and respiratory syncytial virus infections, and elevated SphK1 enhances influenza virus infection. In contrast, SphK1 activity is reduced in bovine viral diarrhea virus and dengue virus infections. Sphingosine analogs that modulate S1P receptors have proven useful in animal models in alleviating influenza virus infection but have shown no benefit in simian human immunodeficiency virus and lymphocytic choriomeningitis virus infections. We have rationalized a role for SphK1/S1P in dengue virus, chikungunya virus, and Ross River virus infections, on the basis of the biology and the pathology of these diseases. The increasing number of effective SphK1 and S1P modulating agents currently in development makes it timely to investigate these roles with the potential for developing modulators of SphK1 and S1P for novel anti-viral therapies.