The sphingolipid messenger ceramide has been implicated in the initiation of apoptotic cell death in a variety of physiologic settings. Recent investigation has shown that ceramide-dependent stress signaling is associated with chemotherapy-related apoptosis. It is not entirely clear, however, whether drug-mediated generation of ceramide is essential for execution of the cell death program, or simply represents a component of the genotoxic stress response. For example, there is evidence that ceramide subserves an important role in certain stresses (e.g., ionizing radiation, daunorubicin) but represents a secondary process in others (e.g., cytarabine). The review presents evidence for and against a cytotoxic effector function for ceramide in the lethal actions of conventional antineoplastic agents.