Background: Fibroblast Growth Factor Receptor 1 (FGFR1) plays an important role in cancer and is an emerging treatment target for squamous lung cancer and other tumor types. We determined the functional implicatiosn of FGFR1 signaling using a systems biology approach. Methods: 120 HNSCC tumor samples from patients treated at Univ. of Chicago were analyzed. We determined copy number alterations (Nanostring, +qPCR validation), gene expression (Agilent) as well as mutations (Illumina)and employed in-silico modeling/published gene expression signatures (GSEA) to investigate receptor kinases as well as mechanisms correlated with FGFR1 signaling. HNC TCGA data was used for validation. Secondly we performed in-vitro validation in a panel of 12 HNSCC cell lines. Viability testing was performed with PD173074, ponatinib, gefitinib, as well as combinations of these drugs. Immunoblotting was performed for MAPK and AKT pathways, Vimentin and E-Cadherin total protein. Results: FGFR1 copy number gain occurred in 3% or our cohort and 8% of TCGA samples and was most prominent in laryngeal tumors. Interestingly high FGFR1 expression were identified in 20% of HNSCC and highly correlated with Epithelial-to-Mesenchymal Transition (EMT) (p<0.001). Several additional receptor Tyrosine Kinases (RTKs) strongly correlated with EMT including PDGFRA, PDGFRB, AXL, and ACVRL1 (TGF-beta pathway). By contrast EGFR and MET expression strongly correlated with an epithelial phenotype. We identified 6 mesenchymal-like and 6 non-mesenchymal-like cell lines out of a panel of 40 cell lines. Mesenchymal cell lines were resistant to Epidermal Growth Factor Receptor-inhibition with gefitinib, but combined FGFR and EGFR inhibition showed strong synergy in these resistant cell lines. Ponatinib showed the highest level of activity, due to evidence of co-inhibition of other EMT associated kinases. Conclusions: FGFR1 drives the EMT phenotype in HNC, and is a valid treatment target that may help overcome EGFR resistance when used in combination.