Recent evidence suggests that tumor necrosis factor alpha, Fas, and ionizing radiation employ the sphingomyelin pathway to trigger apoptosis. The sphingomyelin pathway is initiated by hydrolysis of plasma membrane sphingomyelin to generate ceramide via a sphingomyelinase. Ceramide serves as a second messenger stimulating a cascade of kinases and transcription factors that activate a final common pathway of programmed cell death. The extent to which this signaling system is used in apoptosis induced by other toxic modalities is not known, but accumulating evidence suggests that it is a commonly employed pathway that could be exploited therapeutically.