Epidermal growth factor receptor (EGFR) overexpression is common in head and neck squamous cell carcinoma. Targeted therapy specifically directed towards EGFR has been an area of keen interest in head and neck cancer research, as EGFR is potentially an integration point for convergent signaling. Despite the latest advancements in cancer diagnostics and therapeutics against EGFR, the survival rates of patients with advanced head and neck cancer remain disappointing due to anti-EGFR resistance. This review article will discuss recent multilateral efforts to discover and validate actionable strategies that involve signaling pathways in heterogenous head and neck cancer and to overcome anti-EGFR resistance in the era of precision medicine. Particularly, this review will discuss in detail the issue of cancer metabolism, which has recently emerged as a novel mechanism by which head and neck cancer may be successfully controlled according to different perspectives.