The discovery of specific mutations and associated addicted pathways in lung adenocarcinoma cells has led to the development of many targeted therapies useful for corresponding activating mutation. In addition, conventional chemotherapy and novel immunotherapy such as PD1/PDL1 antibodies are also very effective for lung cancer patients with or without specific driver mutation. Patients with metastatic lung cancer nowadays can be treated with multiple lines of effective treatment. Patients who receive more lines of therapy tend to live longer than those who had only receive limited number of treatment. In order to maximize the overall survival outcome of metastatic lung cancer patient who receives systemic treatment, it is important to find out the best first line choices and the best timing to change the treatment regimen to second line and so forth. Tumor reduction or stabilization by imaging criteria has been used widely for a long time in chemotherapy and targeted therapy era. RECIST (Response evaluation criteria in solid tumors) has been adopted as a uniform criteria for cancer clinical trial to classify the tumor response to certain treatment. However, in order to accommodate different cancer types and sites of metastasis, several variants of RECIST emerged to better evaluate the treatment response and necessity of maintain the present treatment. In daily practice, changes of tumor size in the image provide the best guidance for clinicians to continue or change regimen for the patients. In patients who has no reliable evaluable radiological image for follow up, such as patients who presented with effusion, bone metastasis, leptomeningeal metastasis or tumor with poor margin, patients’ clinical performance and alterations in tumor markers occasionally can provide clinicians information for judgement. The introduction of cell free plasma tumor DNA for the molecular diagnosis of cancer gave us a new change of how to manage the patients properly when changing regimen to prolong patients chance to survive or improving quality of life are attainable. There are a least 3 important applications for cell free tumor DNA detection. First is to provide information of specific mutation at the time of diagnosis or progression, so that a corresponding targeted therapy can be chosen as the best treatment of choice. Second is to use quantitative amount of specific mutation found in plasma cell free DNA to follow patient’s tumor. The presumption is the amount of specific mutation may represent the tumor load of the treated patients. The 3rd possible application is to use the novel mutations detected in the plasma at the time of diagnosis or during treatment follow up to select a theoretical best combination for patients. There are ample of analysis reported in the literature for the first and second possible applications of plasma cell free DNA. The evidence for the 3rd possible application is accumulating. However, there is no emphasis of using this vast information gathered in the plasma to guide the right timing to switch regimen. In addition, there has been a trend to continue original treatment in slow progressing patients beyond imaging progression, or to treat oligo-progressing sites with local irradiation or surgery in order to keep the original treatment. These approaches certainly will further complicate the rationale decision of right timing to change regimen. Thus, a few options exist for patients who are receiving targeted therapies. One is to use conventional ways of RECIST progression by imaging studies to change the treatment to further lines. The treatment outcome may be more predictable, because most of the clinical trials follow this dogma. A second choice is to treat patients beyond progression by RECIST and follow physicians judgment to switch the regimen. Several recent clinical trials use this criteria to change regimen and collect the treatment time as duration-of-treatment, or time-to-treatment-failure. The 3rd possible timing is to switch regimen according to plasma DNA alterations, for example, emergence of activating mutation when plasma tumor DNA was previously eradicated by current targeted therapy; add another targeted therapy when a new parallel pathways amplification is predicted from the plasma sample analysis. This strategy lack the support of prospective clinical trial data and was purely based on direct scientific deduction or instinct and a few case reports. Therefore, studies specifically designed to address the switch timing is very important. Unfortunately, the effort devoted to this area is lacking.