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The dominant paradigm in cancer treatment is that cancer cells die from the common pathway of apoptosis subsequent to DNA damage by anticancer agents and that cells resistant to apoptosis are resistant to therapy. In this review we trace the logic that brought about this view and discuss whether the clinical and experimental data that have now accumulated over the past decade support the position. We show that there is support for the apoptosis model only for certain malignancies of hematopoietic origin. For the majority of cancers (which are of epithelial origin) – even though some may exhibit apoptosis after treatment – there is little or no support for the concept that apoptosis, and the genes that govern it, determine the response to therapy. In general, whether apoptosis matters for overall tumor response depends on how soon after treatment apoptosis occurs. If it occurs early (within 4-–6 hours after …