Advanced head and neck squamous cell carcinomas (HNSCC) are frequently drug resistant and have a mortality rate of 40%. We have previously shown that E2F7 may contribute to drug sensitivity In HNSCC cells. In the present study, we conducted a transcriptomic screen to identify the downstream factors that contribute to E2F7-dependent resistance to anthracyclines in HNSCC. We provide, in vitro, in vivo and patient data that identifies the existence of a novel E2F7/RacGAP1 pathway axis that regulates sensitivity to anthracyclines in HNSCC. Specifically, we show that E2F7-dependent sensitivity to doxorubicin occurs via induction of RacGAP1. We also show that SCC cells deficient in RacGAP1 grow slower in vivo and are sensitized to the cytotoxic actions of doxorubicin in vivo. Finally, we show that RacGAP1 is significantly overexpressed in 73 % of primary and metastatic human SCCs compared with adjacent “normal” tissue. Moreover, we show that HNSCCs that overexpress RacGAP1 are associated with a significantly poorer overall survival. Combined, these findings identify RacGAP1 overexpression as a novel prognostic marker of survival and a driver of drug resistance in HNSCC.