Most lung cancer patients were diagnosed at advanced stage, therefore, local treatment for cure is often impossible. Systemic treatment is the mainstay for advanced stage nonsmall cell lung cancer management. Platinum-based chemotherapy has become standard treatment since 1995. Several new chemotherapy were designed and improved treatment outcome for NSCLC. Since year 2000, small molecules act as targeted therapy has changed the treatment paradigm for NSCLC. Epidermal growth factor inhibitor tyrosine kinase inhibitors have shown high activity in NSCLC patients who failed chemotherapy. Later on, EGFR mutation was identified in patients who had responded well to the EGFR TKI. EGFR mutation frequently occurred in Asian, non-smoking NSCLC patients and was associated with very good response to EGFR TKI and so called “oncogene addiction”. Patients who failed 1st generation reversible EGFR TKIs (gefitinib or erlotinib) or 2nd generation irreversible EGFR TKIs (afatinib) can develop resistant mutations at T790M. Those patients can respond very well to 3rd generation mutant specific EGFR TKI, osimertinib. ALK, ROS1, RET gene rearrangements were discovered in small fraction of patients with lung cancer. These gene rearrangement products, fusion proteins contain activating kinases and transform normal cells into cancer cells. Specific inhibitors to these kinases can control the growth of the cancer cells resulted in good response of the tumor. Other identified specific mutations in NSCLC included B-raf mutations, cMET skipping exon 14 mutation, HER2 mutation and K-ras mutation. Interestingly, these mutations are usually mutually exclusive in each patients, i.e. each patient only harbor one driver mutation. Thus, detecting the driver mutation and provide specific inhibitors to patients are of vital importance for best control of patient’s cancer. In the past few years, the discovery of program death-1 on cytotoxic T cells and program death 1 ligand in cancer cells being the inhibitory checkpoint for cancer cells to evade from immune cells attack provided the rationale to develop monoclonal antibodies against PD1/PDL1 to restore T cells activity against tumors. 10-15% of NSCLC patients had good response to PD1 or PDL1 inhibitors. Recently, several studies indicated that combination of checkpoint inhibitors and chemotherapy can improve overall survival of NSCLC patients over chemotherapy alone. The 5 year survival of stage IV NSCLC have improved from 3% to over 10% in the past 15 years. Advances in our knowledge of the tumor cells and micro-environment may further improve patient’s survival and quality of life in the future.