How do antineoplastic therapies cure cancer? Longstanding dogma held that such treatments selectively target rapidly dividing cells. We see in the clinics, however, that this explanation is not satisfactory since curable cancers may be relatively slow growing and many rapidly dividing cancers are resistant to treatment. Emerging evidence suggests that, owing to varying apoptosis thresholds, treatments may induce apoptosis in tumor cells, but merely a cell cycle pause in their normal cell counterparts. Correspondingly, a major mode of resistance to antitumor treatments may be insensitivity to apoptosis induction. These conclusions stem from studies of select cell types, oncogenes, and apoptosis triggers. Their applicability to most human cancers, if verified, stands to revolutionize our approach to cancer therapy. Apoptosis is a genetically encoded cell death program defined by characteristic morphologic and biochemical changes (Wyllie, 1985, and references therein). A multitude of factors modulate apoptosis induction, including growth factors, intracellular mediators of signal transduction, and nuclear proteins regulating gene expression, DNA replication, and cell cycle. These diverse factors and pathways likely converge on common late steps, resulting in the characteristic apoptosis phenotype. Apoptosis is a pathway that may potentially be disrupted in tumor cells, conferring a survival advantage. Apoptosis also directly regulates tumorigenesis. Dissection of multistep oncogenesis in colorectal cancer revealed frequent aberrations of the p53 gene (for reviews see Vogelstein and Kinzler, 1992; Harris and Hollstein, 1993, and references therein), now one of the most commonly detected abnormalities in human cancer and recognized as an important modulator of apoptosis. As reported by Symonds et al.(1994 [this issue of Ce//)), one of~ 53’s roles in regulating tumorigenesis may involve its ability to induce apoptosis in the presence of oncogenic triggers. Induction of aggressive choroid plexus tumors by a fragment of T antigen depended on the absence of~ 53. Tumors induced by this weak oncogene developed much more rapidly in~ 53 knockout mice than in mice with wild-type~ 53; heterozygous mice (p53+‘-) developed aggressive tumors that lacked wild-type~ 53. Loss of p53dependent apoptosis correlated with tumor aggressiveness. This pattern is reminiscent of patients with Li-Fraumeni syndrome, who are constitutively heterozygous for p53 (Malkin et al., 1990) and who develop tumors with high frequency. If resistance to apoptosis were tied to both oncogenesis and therapeutic response, it may be clear why cancer is so difficult to cure.