The identification of molecular agents inhibiting specific functions in cancer cells progression is considered as one of the most successful plans in cancer treatment. The epidermal growth factor receptor (EGFR) over-activation is observed in a vast number of cancers, so, targeting EGFR and its downstream signaling cascades are regarded as a rational and valuable approach in cancer therapy. Several synthetic EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in recent years, mostly exhibited clinical efficacy in relevant models and categorized into first, second, third and fourth-generation. However, studies are still ongoing to find more efficient EGFR inhibitors in light of the resistance to the current inhibitors. In this review, the importance of targeting EGFR signaling pathway in cancer therapy and related epigenetic mutations are highlighted. The recent advances on the discovery and development of different EGFR inhibitors and the use of various therapeutic strategies such as multi-targeting agents and combination therapies have also been reviewed.