Sphingolipid-metabolizing enzymes are becoming targets for chemotherapeutic development with an increasing interest in the recent years. In this chapter we introduce the sphingolipid family of lipids, and the role of individual species in cell homeostasis. We also discuss their roles in several rare diseases and overall, in cancer transformation. We follow the biosynthesis pathway of the sphingolipid tree, focusing on the enzymes in order to understand how using small molecule inhibitors makes it possible to modulate cancer progression. Finally, we describe the most used and historically significant inhibitors employed in cancer research, their relationships to sphingolipid metabolism, and some promising results found in this field.