The incidence and mortality of lung cancer rank top three of all cancers worldwide. Accounting for 85% of the totalnumber of lung cancer, non-small cell lung cancer (NSCLC) is an important factor endangering human health.Recently, targeted therapies against driver mutations and epigenetic alterations have made encouraging advancesthat benefit NSCLC patients. Druggable driver mutations, which mainly occur inEGFR,KRAS,MET,HER2,ALK,ROS1,RETandBRAF,havebeenidentified in more than a quarter of NSCLC patients. A series of highly selec-tive mutant targeting inhibitors, such as EGFR tyrosine kinase inhibitors and KRAS inhibitors, have been well stu-died and applied in clinical treatments, which greatly promote the overall survival of NSCLC patients. However,drug resistance has become a major challenge for targeted treatment, and a variety of methods to overcome drugresistance are constantly being developed, including inhibitors against new mutants, combination therapy with otherpathway inhibitors, etc. In addition, epigenetics-based therapy is emerging. Epigenetic regulators such as histonedeacetylases and non-coding RNA play a crucial role in the development of cancer and drug resistance by affectingmultiple signaling pathways. Epigenetics-based therapeutic strategies combined with targeted drugs show great clin-ical potential. Many agents targeting epigenetic changes are being investigated in preclinical studies, with somealready under clinical trials. This article focuses on driver mutations and epigenetic alterations in association withrelevant epidemiological data. We introduce the current status of targeted inhibitors and known drug resistance,review advances in major targeted therapies with recent data from preclinical and clinical trials, and discuss the pos-sibility of combination therapy against driver mutations and epigenetic alterations in overcoming drug resistance.