p53 is a transcription factor activated by genotoxic stress. Dependent on the level of DNA damage, p53 can either trigger cell cycle arrest and DNA repair or programmed cell death. DNA damaging agents that activate p53 are commonly used in the treatment of cancer. If p53 inducible proteins that promote arrest and repair and inhibit apoptosis are up-regulated, tumours can become resistant to many types of treatment (multidrug resistance, MDR). MDR leads to treatment failure, metastases, and death in breast cancer patients. It is especially important in patients who rely solely on chemotherapy because they do not express hormone receptors and thus, do not benefit from endocrine therapies (e.g. tamoxifen). We have generated a triple-negative doxorubicin resistant breast cancer cell line (CALDOX) and shown by RNA array and qPCR analysis that p53-inducible cell survival factor (p53CSV), a p53-inducible inhibitor of apoptosis, is up-regulated in CALDOX and inducible by doxorubicin. Transient knockdowns of p53CSV sensitised CALDOX cells to doxorubicin, but stable knockdowns failed to support this preliminary data. However, CALDOX cells maintained expression of arrest and repair proteins p21 and p53CSV at high levels of genotoxic stress by doxorubicin—while CAL51 cells induced apoptotic protein p53AIP1 and underwent apoptosis. Although it is unlikely that p53CSV acts as a sole factor in MDR in CALDOX cells, p53CSV and other p53 arrest and repair proteins are likely an important factor in MDR through the evasion of apoptosis and promotion of DNA repair in CALDOX cells. Interestingly, we find that p53CSV is widely expressed in normal healthy tissues, conserved across eukaryotes, and in CAL51 cells, only partially p53-dependent—indicating that p53CSV may have an important role separate of p53, perhaps in the control of proliferating cells during development.