Background: In head and neck squamous cell carcinoma (HNSCC), resistance to single agent targeted therapy may be overcome by co-targeting of compensatory signaling pathways. Methods: A targeted drug screen with 120 combinations was used on 9 HNSCC cell lines. Results: Multiple novel drug combinations demonstrated synergistic growth inhibition. Combining the insulin-like growth factor-1 receptor (IGF1R) inhibitor BMS754807 with either the HER-family inhibitor BMS599626 or the Src-family kinase inhibitor dasatinib resulted in substantial synergy and growth inhibition. Depending on the cell line, these combinations induced synergistic or additive apoptosis; when synergistic apoptosis was observed, AKT phosphorylation was inhibited to a greater extent than either drug alone. Conversely, when additive apoptosis occurred, AKT phosphorylation was not reduced by the drug combination. Conclusions: Combined IGF1R/HER family and IGF1R/Src family inhibition may have therapeutic potential in HNSCC. AKT may be a node of convergence between IGF1R signaling and pathways that compensate for IGF1R inhibition. Head Neck, 2014.