AbstractBackgroundGenomic rearrangement in anaplastic lymphoma kinase (ALK) gene occurs in 3−7% of patients with non-small-cell lung cancer (NSCLC). The detection of this alteration is crucial asALKpositive NSCLC patients benefit fromALKinhibitors, which improve both the patient's quality of life and overall survival (OS) compared to traditional chemotherapy.ContentIn routine clinical practice,ALKrearrangements are detected using tissue biopsy. Nevertheless, the availability of tumor tissue is compromised in NSCLC patients due to surgical complications or difficult access to the cancer lesion. In addition, DNA quality and heterogeneity may impair tumor biopsies testing. These limitations can be overcome by liquid biopsy, which refers to non-invasive approaches for tumor molecular profiling. In this paper we review currently available technology for non-invasiveALKtesting, in NSCLC patients, based on the analysis of circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), circulating tumor cells (CTCs), tumor-educated platelets (TEPs) and extracellular vesicles (EVs) such as exosomes.Summary and outlookNon-invasive tumor molecular profiling is crucial to improve outcomes and quality of life of NSCLC patients whose tumors harbor a translocation involvingALKlocus.