We started writing this review based on a question, “can modulating the SphK-S1P-S1PR pathway reduce severe COVID-19 disease symptoms?” From historical and contemporary data on the involvement of the sphingolipid pathway in viral infections, inflammation, and vascular integrity there is strong support demonstrating a role for modulating components of the SphK-S1P-S1PR in COVID-19 disease management. This evidence concerns the gene MBTPS1 and COVID-19.