Lung cancer is the leading cause of cancer-related mortality worldwide. The discovery of tyrosine kinase inhibitors effectively targeting EGFR mutations in lung cancer patients in 2004 represented the beginning of the precision medicine era for this refractory disease. This great progress benefits from the identification of driver gene mutations, and after that, conventional and new technologies such as NGS further illustrated part of the complex molecular pathways of NSCLC. More targetable driver gene mutation identification in NSCLC patients greatly promoted the development of targeted therapy and provided great help for patient outcomes including significantly improved survival time and quality of life. Herein, we review the literature and ongoing clinical trials of NSCLC targeted therapy to address the molecular pathways and targeted intervention progress in NSCLC. In addition, the mutations in EGFR gene, ALK rearrangements, and KRAS mutations in the main sections, and the less common molecular alterations in MET, HER2, BRAF, ROS1, RET, and NTRK are discussed. The main resistance mechanisms of each targeted oncogene are highlighted to demonstrate the current dilemma of targeted therapy in NSCLC. Moreover, we discuss potential therapies to overcome the challenges of drug resistance. In this review, we manage to display the current landscape of targetable therapeutic patterns in NSCLC in this era of precision medicine.© 2022. The Author(s).