An astute observer of chemotherapeutic progress concedes that anticancer research is, in effect, often more empirical that rational, and there are those who maintain that little gain has been made in the therapeutic outcome of cancer patients in the past 60 years, thus, questioning the wisdom of continued expenditure of funds for research in cancer chemotherapy. Half a decade ago few would have denied the importance of regarding the intimate drug-target interactions in cell death or in resistance thereof. However, the heretofore-parochial approach to drug screening and rationalization of structure-activity based on specific drug-target interactions has met with limited success. This standpoint has forced investigators to explore new and certainly provocative interpretations, which necessitate radical departure from accepted but perhaps outworn concepts of the action of drugs. The recent identification of a ceramide mediated apoptotic signaling pathway triggered by antitumor agents may offer new insights into mechanism of action of chemo- and radio-therapy. This review is intended to initiate a debate on the role of ceramide in apoptosis signaling: is it a consequence of cell damage, or part of an independent cytotoxic pathway ?