The over expression of EGFR has been recognized as the driver mechanism in the occurrence and progression of carcinomas such as lung cancer, breast cancer, pancreatic cancer, etcetera. EGFR receptor was thus established as an important target for the management of solid tumors. The occurrence of resistance caused as a result of mutations in EGFR has presented a formidable challenge in the discovery of novel inhibitors of EGFR. This has resulted in the development of three generations of EGFR TKIs. Newer mutations like C797S cause failure of Osimertinib and other EGFR TKIs belonging to the third-generation caused by the development of resistance. In this review, we have summarized the work done in the last five years to overcome the limitations of currently marketed drugs, giving structural activity relationships of quinazoline-based lead compounds synthesized and tested recently. We have also highlighted the shortcomings of the currently used approaches and have provided guidance for circumventing these limitations. Our review would help medicinal chemists streamline and guide their efforts towards developing novel quinazoline-based EGFR inhibitors.