Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a clinically useful cytokine. TRAIL induces apoptosis in a wide variety of transformed cells, but does not cause toxicity to most normal cells. Recent studies show that death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and death inhibitors (FLIP, FAP-1, and IAP) are responsible for the differential sensitivity to TRAIL of normal and tumor cells. Several researchers have also shown that genotoxic agents, such as chemotherapeutic agents and ionizing radiation, enhance TRAIL-induced cytotoxicity by increasing DR5 gene expression or decreasing the intracellular level of FLIP, an antiapoptotic protein. Previous studies have shown that ceramide helps to regulate a cell's response to various forms of stress. Stress-induced alterations in the intracellular concentration of ceramide occur through the activation of a variety of enzymes that synthesize or catabolize ceramide. Increases in intracellular ceramide levels modulate apoptosis by acting through key proteases, phosphatases, and kinases. This review discusses the interaction between TRAIL and ceramide signaling pathways in regulating apoptotic death.