Patient mortality rates have remained stubbornly high (40%) for the past 35 years in head and neck squamous cell carcinoma (HNSCC) due to inherent or acquired drug resistance. Thus, a critical issue in advanced SCC is to identify and target the mechanisms that contribute to therapy resistance. In this study we report that the transcriptional inhibitor, E2F7, is mislocalized to the cytoplasm in > 80 % of human HNSCCs whilst the transcriptional activator, E2F1, retains localization to the nucleus in SCC. This leads to an imbalance in the control of E2F-dependent targets such as Sphk1 which is derepressed and drives resistance to anthracyclines in HNSCC. Specifically, we show that i) E2F7 is subject to XPO1-dependent nuclear export, ii) E2F7 is selectively mislocalized in the majority of SCC and multiple other tumor types, iii) mislocalization of E2F7 in HNSCC causes derepression of Sphk1 and drives anthracycline resistance and iv) anthracycline resistance can be reversed with a clinically available inhibitor of XPO1, selinexor, in xenotransplant models of HNSCC. Thus, we have identified a strategy to repurpose anthracyclines for use in SCC. More generally, we provide a strategy to restore the balance of E2F1 (activator) and E2F7 (inhibitor) activity in cancer.