Sphingolipids, including ceramide and sphingosine-1-phosphate (S1P), play dual roles in cancer cell death and survival. Recent studies have elucidated how sphingolipid metabolism and signaling regulate these processes in response to anticancer therapy. Ceramide, a key sphingolipid, induces cellular stress and mediates cancer cell death through various mechanisms, including apoptosis, necroptosis, and mitophagy. S1P, derived from ceramide metabolism, has pro-survival functions and influences cancer cell growth, drug resistance, and metastasis through S1P receptor (S1PR)-dependent or receptor-independent signaling. Targeting enzymes involved in sphingolipid metabolism and signaling offers promising therapeutic strategies. Clinical trials are evaluating the potential of therapeutic approaches targeting these enzymes in various tumor types. This review discusses recent mechanistic and clinical studies that have advanced our understanding of sphingolipids in cancer biology and therapeutics, focusing on their roles in cell death, proliferation, and metastasis, as well as their implications for cancer immunology and immunotherapy.Sphingolipids, including ceramide and sphingosine-1-phosphate (S1P), play dual roles in cancer cell death and survival. Recent studies have elucidated how sphingolipid metabolism and signaling regulate these processes in response to anticancer therapy. Ceramide, a key sphingolipid, induces cellular stress and mediates cancer cell death through various mechanisms, including apoptosis, necroptosis, and mitophagy. S1P, derived from ceramide metabolism, has pro-survival functions and influences cancer cell growth, drug resistance, and metastasis through S1P receptor (S1PR)-dependent or receptor-independent signaling. Targeting enzymes involved in sphingolipid metabolism and signaling offers promising therapeutic strategies. Clinical trials are evaluating the potential of therapeutic approaches targeting these enzymes in various tumor types. This review discusses recent mechanistic and clinical studies that have advanced our understanding of sphingolipids in cancer biology and therapeutics, focusing on their roles in cell death, proliferation, and metastasis, as well as their implications for cancer immunology and immunotherapy.