The era of sphingolipid-based therapeutics is upon us. A large body of work has been accumulating that demonstrates the distinct biological roles of sphingolipids in maintaining a homeostatic environment and in responding to environmental stimuli to regulate cellular processes. It is thus necessary to further investigate alterations in sphingolipid-metabolism in pathological conditions and, in turn, try to exploit altered sphingolipid-metabolizing enzymes and their metabolites as therapeutic targets. This review will examine how advances in the fields of drug delivery, drug discovery, synthetic chemistry, enzyme replacement therapy, immunobiology, infectious disease and nanotechnology have delivered the potential and promise of utilizing and/or targeting sphingolipid metabolites as therapies for diverse diseases.