Given the number of ongoing clinical trials testing the use of EGFR TKIs in HNSCC patients, there is a greater need to understand the mechanisms of resistance to EGFR TKIs in order to improve the efficacy of these agents, to develop optimal combinatorial therapies, and to select patients (based on biomarkers) who will likely benefit from EGFR TKIs. Here, EGFR is linked to head and neck squamous cell carcinoma.