The effect of TP53 mutations on chemosensitivity in breast cancer is a controversial issue. In an elegant paper in Cancer Cell, Jackson and colleagues report wtp53 protein to block anti-tumour effects of doxorubicin treatment in mice. p53 did so by inducing senescence, thereby preventing mitotic catastrophy and subsequent cell death. In contrast, while TP53 mutations have shown to predict response to cyclophosphamide high dose therapy, mutations in general have been associated with anthracycline resistance in human breast cancers. The challenging results from Jackson and colleagues' study elucidate a new hypothesis and suggest directions for future translational research in human breast cancer.