Several recent studies showed that EML4-ALK rearrangement could be detected within CTCs . In 2012 a study from our group showed very good agreement between the presence of EML4-ALK rearrangements in tissue biopsies and in CTCs . In this study, detection of CTCs was performed with a direct method (ISET) using filtration of blood through a porous filter which retained on its surface CTCs that are larger than circulating hematological cells. The ISET method used in this work has the advantage of being able to characterize the cyto-morphology of the isolated CTCs and the malignant cytological criteria can be used to identify the different populations of cells on the surface of the filter . Moreover, this approach holds the advantage of allowing correlation between the ALK status, determined by ICC and/or FISH and the malignant cytological characteristics which limits potential false positive results. In this context, since it was reported that ICC and FISH analyses gave the same results, the question was to know if ICC can be used for systematic rapid screening of ALK status in isolated CTCs. In fact, ICC results can be easily interpreted by cytopathologists in any pathology laboratory and performed in an identical way to detection of ALK rearrangements using tissues or cells. However, despite the promising results from the initial study, one limitation was that only a small number of patients at a single center were studied . In this regard, a French multi-center study with a large number of patients with a tissue biopsy ALK positive status is now in progress  (www.clinicaltrials.gov/ct2/show/NCT02372448). Another limitation of the initial study was that no information existed concerning a possible association between targeted treatments for patients presenting with ALK positive CTCs and the therapeutic response, in particular with respect to the CTC number. Finally, some patients often had less than 100 analyzable CTCs, which make the interpretation of a positive score difficult to take into consideration. A second study using the ISET method also showed a correlation between the presence of an EML4-ALK rearrangement in tissues and CTCs and a correlation with the disappearance of CTCs with a good response to targeted therapy . The analysis with immunofluorescence and confocal microscopy demonstrated that CTCs harboring a unique ALK rearrangement may have a mesenchymal phenotype with the potential to drive metastatic progression of ALK-positive NSCLC . Using the same ISET method for CTCs detection, a recent study looked for the prognostic value of patients with CTCs having ALK-copy number gain (CNG) at baseline and treated with crizotinib . In this study, the dynamic change in the numbers of CTCs with ALK-CNG was a predictive biomarker for crizotinib efficacy in ALK-rearranged NSCLC patients . Another study confirmed the correlation between a positive EML4-ALK status detected in tissues and in CTCs detected by FISH analysis . This latter study showed that persistence of or an increase in the number of ALK positive CTCs on FISH analysis correlated with tumor progression in patients on treatment with crizotinib, in particular with the appearance of a new molecular profile . Finally, a recent work demonstrated that ALK-rearrangement can also be detected in CTCs collected from advanced NSCLC patients by another approach, the NanoVelcro system .