Sphingolipids, particularly their two main bioactive metabolites ceramide and sphingosine-1-phosphate (S1P), play a key role in cancer death and survival. Ceramides induce cancer cell death through apoptosis, autophagy, or necroptosis. S1P on the other hand inhibits apoptosis and stimulates proliferation, migration, metastasis, and drug resistance via receptor-dependent or receptor-independent pathways. Modulating the cellular sphingolipidome, through targeting specific enzymes or metabolites, is emerging as a promising pharmacological intervention that could limit cancer progression and improve disease outcomes. In this chapter, we highlight new pharmacological tools that have the potential to modulate key sphingolipid enzymes and metabolites to be used in cancer treatment.