Sphingolipids, a major class of lipids in cell membranes, play diverse roles in biological processes. As bioactive and structural molecules, they have signaling activities and biophysical properties that are essential for regulating various cellular, tissue and systemic functions. Moreover, sphingolipids are receiving increasing attention as contributors to the pathogenesis of several human disorders, including, cancer, inflammation and neurological, immune and metabolic disorders. Small-molecule inhibitors and monoclonal antibodies that target sphingolipid metabolism recently enabled giant strides toward treatment of malignant and autoimmune disorders. Here, we review the emerging roles of sphingolipids in disease pathogenesis and the attendant possibilities for sphingolipid-based therapeutics.