Non-small cell lung cancer (NSCLC), mainly adenocarcinoma subtype, can carry different types of oncogenic driver mutations. EGFR mutations are present in up to 50% of lung adenocarcinomas from the Asian population. EGFR-tyrosine kinase inhibitor (EGFR-TKI) should be used as primary treatment of lung cancer bearing sensitizing EGFR mutations, namely 15-base pair deletion at exon 19, or L858R or L861Q mutations at exon 21. First- and second-generation EGFR-TKIs have greatly improved the treatment of EGFR mutant lung cancer. However, the majority of patients who respond initially will eventually experience treatment failure with disease progression. In patients who develop acquired resistance to EGFR-TKI, 50% of them showed a second EGFR T790M mutation at exon 20. ALK gene rearrangement is not common in lung cancer, less than 7%, but once detected, upfront ALK-inhibitors use is associated with good therapeutic efficacy. ALK mutations have been found to be involved with acquired resistance to ALK-inhibitors. PD-L1 expression scoring, however, is difficult to unify and thus hindering it’s potential to be a good clinical therapeutic biomarkers. The use of immune check-point inhibitors, targeting the detection of PD-L1 expression on lung tumor cells, has found increasing support from clinical trials for being used alone or in combination with chemotherapy in advanced stage NSCLC, or to follow chemo-irradiation in unresectable stage III NSCLC. Third-generation EGFR-TKI targeting EGFR T790M mutation has been approved for treatment of lung tumors bearing EGFR T790M mutation. Demonstration of EGFR T790M mutation through repeat tumor biopsy after treatment is, however, not always feasible at disease progression. Liquid biopsy may help in such situation. Although much is known about these therapeutic biomarkers and drugs that overcome resistance are already approved for clinical use, much more research is needed to explore biomarkers of better predictive and prognostic performance and to guide therapy. Molecular testing for lung cancer biomarkers is not limited to testing in tumor tissues. Liquid biopsy in the form of biomarker detection on cell free tumor DNA in plasma, using different molecular biology methods, is a rapidly developing field. The identification of biomarkers will support the practice of personalized medicine and this will be closely tied to the understanding of biology and molecular progression of lung neoplasms. Heterogeneity of lung tumors may imply the presence of different malignant cell types in a suspicious lesion. Liquid biopsy aims at analysis of circulating biomarkers in peripheral blood, such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). These act as alternative or supplementary source of cancer-derived information that may be able to overcome the issue of representativeness of a small biopsy out of a sizable tumor. All these research adventures will hopefully advance our understanding into the application of therapeutic biomarkers in lung cancer.