The N-terminal portion of the protein encoding microtubule-associated protein-like 4 (EML4) in echinoderms is fused to the intracellular tyrosine kinase structural domain of mesenchymal lymphoma kinase (ALK) and rearranges to EML4-ALK, resulting in aberrant tyrosine kinase expression. EML4-ALK rearrangement fusion was first detected by Soda in 2007 in postoperative specimens from patients with non-small cell lung cancer. Since then, it has been reported in the United States, Japan, Korea and Hong Kong, China, but the positive detection rate of EML4-ALK in unselected NSCLC is low, about 1.5-6.7%. To improve the detection rate of this fusion gene, Shaw et al. set the study to enroll patients who had to have two or more of the following characteristics: female, Asian, no or only a small history of smoking, and adenocarcinoma. The results showed that 19 of 141 patients (13%) were EML4-ALK positive, and the EML4-ALK positivity rates were as high as 22% and 33% for non-smokers or only light smokers/and those without EGFR mutations, respectively, which is the highest reported EML4-ALK detection rate to date. The results of this study suggest that EML4-ALK screening must be focused, and that these EGFR-TKI-advantaged but insensitive populations may harbor new molecular events and may be the target population for future ALK-targeted therapies in clinical practice. From the results of previous studies and the two aforementioned papers, there were no major differences between the eastern and western populations or between different races and countries in EML4-ALK fusion positive patients, and the clinicopathological characteristics were similar. As for the differences shown by age and gender in single center studies need to be verified in more samples. The current status of EML4-ALK research and worthy of attention are: 1. Whether different fusion gene types have different clinical features and treatment response and prognosis EML4-ALK is caused by insertion of the short arm of chromosome 2, and several variant types have been identified so far. The study by Takahashi et al. from Japan identified new fusion gene types, but the number of cases was small and did not reflect more information, so we are looking forward to clarifying whether different fusion gene types have different clinical characteristics and treatment response and prognosis as the testing population becomes more extensive in the future. 2. Single-center retrospective study The study by Takahashi et al. included more than 300 patients for testing, which is the largest reported sample analysis to date. However, the vast majority of previous studies have been single-center, retrospective studies. In order to avoid bias caused by ethnic, geographical and clinical imbalances, multicenter, large-sample prospective studies are urgently needed in the future. 3, different testing methods in each center Just like all the initial stages of testing indicators, we must carefully and objectively analyze the differences in results due to different testing methods in each center, and optimize the best testing techniques from them, and standardize and popularize them as soon as possible to make the results comparable. The prognostic value of EML4-ALK has yet to be determined. The prognostic impact of EML4-ALK on NSCLC needs more in-depth observation because of the short follow-up time for early stage cases and the diverse and complex treatment for late stage cases. 5. Whether EML4-ALK is a separate or associated molecular event In 2007, Japanese researchers found that chromosomal rearrangements formed by the fusion of ALK and EML4 genes in some adenocarcinomas could lead to lung adenocarcinoma. Then we wonder whether EML4-ALK positivity is a cause or a consequence of lung adenocarcinoma? And is the recombination of EGFR and K-ras wild type with EML4-ALK gene a necessity of the same molecular event or a coincidence of different molecular events? The above questions also require testing additional molecular indicators other than EML4-ALK in a broader population (including different races, ages, genders, pathological types and different stages of the disease) to discover and reveal the nature of these different molecular events and their associations with each other. Although the existing studies show that the proportion of positive patients carrying EML4-ALK in non-selective NSCLC is low, due to its unique clinical features and molecular pathology, it is not too much to call it a molecular event with small probability and large significance, and its clinical significance and research insights are as follows: 1. The clinical features of EML4-ALK-positive patients are similar to those of EGFR mutants, but the former do not benefit from EGFR -TKI-targeted therapy. Therefore, for patients to be treated with TKI, KRAS mutation status can be tested first, and EGFR mutation testing can be performed for KRAS-negative patients after excluding positive ones; if EGFR mutation is positive, TKI therapy is selected, and negative ones continue with EML4-ALK testing; if EML4-ALK-positive ones, targeted therapy against ALK needs to be tried. Thus, we believe that EML4-ALK is a further enrichment and improvement of the stepwise detection of genetic variants in NSCLC, and we hope that based on this systematic and refined identification, patients with different molecular characteristics can receive the most individualized treatment. 2. With a clear target and mechanism of action, Crizotinib (PF02341006), a small molecule inhibitor targeting the ALK gene, has shown good efficacy in phase I clinical trials. At the recently concluded 46th ASCO Annual Meeting, Bang et al. reported the results of a clinical trial of Crizotinib in advanced NSCLC. The study used fluorescence in situ hybridization (FISH) to detect patients carrying ALK fusions. 82 patients with NSCLC carrying ALK fusions were enrolled, with a median number of three prior treatments. All patients received Crizotinib 250 mg bid orally, and the results showed an objective remission rate of 57% with a duration of remission of 1-15 months. >The 8-week disease control rate (DCR) was 87%, and approximately 72% of patients had no disease progression at 6 months. The investigators concluded that Crizotinib treatment has a high remission rate and a good safety profile in MSCLC patients carrying the EML4-ALK fusion gene. Several clinical trials related to Crizotinib are currently underway, and we look forward to the early release of another new member of molecularly targeted therapies. Compared to other molecular targets and targeted drugs, the research journey of EML4-ALK is just beginning, and although there is still much work to be done, we are really excited and pleased with the results available. In just a few years, we have completed the nearly 40-year journey of EGF→EGFR→EGFR-TKI. We have reason to believe that EML4-ALK fusion gene, as another molecular marker for lung cancer with unique clinical characteristics, indicates that targeted therapy against ALK will lead to more precise and effective individualized treatment for lung cancer and will gradually become mature and perfect.