Erlotinib is a commonly used molecular-targeted drug for the treatment of tongue cancer. However, the development of acquired resistance to erlotinib hampers its therapeutic use.To analyze the erlotinib resistance, long-term and short term survival assay were used to compare the resistance between parental and resistant tongue cancer cells. Flow cytometry, Hochest staining and western blot were used to analyze the apoptosis among the cells. Moreover, Transwell and wound healing assay were used to compare the invasion ability of the cells. To deeply explore the drug resistance in vivo, orthotopic tumor studies were applied. Finally, to explain the mechanism of c-met in erlotinib resistance, shRNA against c-met was used to down-regulate the expression of c-met. And SU11274 also used in orthotopic model.We established erlotinib-resistant human tongue cancer cell line by chronic exposure of TCA-8113 cells to increasing concentrations of erlotinib and determined the role of c-MET and EGFR in the development of acquired resistance. We found a significant increase in the phosphorylation of c-MET and an obvious decrease of the phosphorylation of EGFR in erlotinib-resistant cells. Our results also revealed that inhibition of c-MET alone with SU11274 exerted an inhibitory effect on the proliferation of erlotinib-resistant cells in the short term; however, it failed to sustain the inhibitory effect in the long term. Simultaneous inhibition of c-MET and EGFR significantly inhibited the proliferation of erlotinib-resistant cells in both a short and long period. Furthermore, we explored the underlying mechanism and found that treatment of erlotinib-resistant cells with SU11274 or shRNA against c-MET induced the phosphorylation of EGFR. Moreover, our results demonstrated that simultaneous inhibition of c-MET and EGFR significantly inhibited the migration and invasion of erlotinib-resistant cells.Taken together, our results suggested that c-MET is involved in acquired drug resistance to erlotinib and that cotargeting of EGFR and c-MET could overcome acquired resistance to erlotinib and inhibit the invasion and metastasis of erlotinib-resistant cells.