Despite frequent responses to chemotherapy, curative treatment remains elusive for the majority of patients with metastatic solid tumors. By contrast, in testicular cancer, gestational choriocarcinoma, Hodgkin disease and high-grade lymphomas, chemotherapy is routinely curative, even for patients who present with widely disseminated disease. In the common advanced cancers, however, over 40 years of cytotoxic drug development has brought no significant change in cure rates. One interpretation is that the intrinsic properties of the malignancies themselves, rather than the qualities of individual drugs or combination therapies, are primarily responsible for their curability with chemotherapy. We suggest that the curability of these malignancies results from an intrinsic 'locked-in' state of sensitivity to proapoptotic stresses in these cells. A common property of such curable malignancies is that they arise from cells that undergo major genetic rearrangements or recombination as part of their normal physiology. The absence of further genetic and epigenetic changes in genes that regulate apoptosis, DNA repair and senescence allows these cells to maintain their intrinsic sensitivity to chemotherapy. This process allows the cells, when challenged with chemotherapy, to undergo the natural apoptotic pathways that contribute to their intrinsic qualities of chemosensitivity and high curability.