The development and clinical application of TK domain inhibitors (TKIs) provide important insights into the broader field of cancer-targeted therapies. To discuss the recent advances in the atomic level understanding of EGFR TK domain mutations, we aim at highlighting the current and future importance of these studies on malignancies where the TK domain is improperly activated. The analysis is conducted on published TK domain crystal structures deposited in the Protein Data Bank, or homology structures generated by homology modeling and AutoDock 4.2 software using the program O. Mutations in exon 19 are the most common pathogenic mutations, so the crystal structures with these mutations are analyzed and compared in detail. In addition, we demonstrate how these crystal structures of EGFR conformation with TK domain mutations and those binding with small molecule inhibitors unveil the active or inactive mechanisms. As to the increasing resistance to the TKI, we summarize the progress on overcoming this challenge. Simultaneously, we predict the structure of BIKW-2992 binding to EGFR and compare it with the validated structure of HKI-272. It is hoped that a more accurate resistance mechanism would be found. In brief, we believe that this research will provide insights into EGFR targeted therapies.