Epidermal growth factor inhibition (EGFR) is emerging as an important treatment modality in several epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite some notable successes, less than 20% of patients respond to EGFR inhibition due to intrinsic and acquired resistance. Since EGFR inhibition is already used for lung, colorectal, breast and pancreas cancers in addition to HNSCC, overcoming treatment resistance would have a major impact on outcome. When the mechanisms of intrinsic resistance are identified, including mutations in the EGFR receptor, alternative therapeutic approaches should be employed. Mechanisms of acquired resistance that may be amenable to pharmacological therapies include dysregulation of EGFR degradation, constitutive activation of overlapping signal transduction pathways, especially cMET/HER3, the PI3K/Akt resistance pathway, angiogenesis and epithelial to mesenchymal transition. COX-2 is another promising target for HNSCC and preclinical data suggest that COX-2 inhibitors can affect most of the described acquired EGFR resistance pathways. Several combined EGFR and COX-2 inhibition trials have been completed and demonstrate promise for HNSCC. Combinatorial strategies of combined inhibition of EGFR and acquired resistance pathways in combination with radiation or chemotherapy are warranted.