Nowadays, EGFR-TKIs are important treatment strategy in lung cancer, but the resistance to EGFR-TKIs remains an unsolved issue preventing the patients from further benefits. Recent studies have shown that casein kinase (CK2) plays an important role in carcinogenesis and development of cancer. CK2 inhibitor has also demonstrated anti-tumor effects. Here we reviewed the mechanism of EGFR-TKIs and the potential reasons of resistance. Interestingly, there is a crosstalk between CK2 and EGFR downstream signaling pathways, therefore, it may be possible that CK2 inhibitor can overcome the EGFR-TKIs resistance.