NTRK2 is a receptor tyrosine kinase (TK) that upon brain-derived growth factor (BDGF) and neurotrophin 4/5 (NT-4/5) binding phosphorylates itself and members of the MAPK pathway. It plays a key role in central and peripheral nervous system development as well as in cell survival. Translocations affecting the NTRK2 gene have been reported in several cancer types, including glioblastomas, pilocytic astrocytomas, head and neck squamous cell carcinoma, and lung adenocarcinoma. NTRK2 rearrangements result in the fusion of the 3‘ end of the NTRK2 gene with the 5‘ end of different activating genes (AGBL4, PAN3, or AFAP1). All these fusion genes encode hybrid proteins comprising the TK domain of NTRK2 and the N-terminus of the partner proteins encoding dimerization domains which results in ligand-independent TK activity. Currently, there are several ongoing clinical trials involving drugs with known inhibitory activity of NTRK-related kinases. Entrectinib and LOXO-101 represent two of these TRK inhibitors which have shown promising activity and good tolerability in patients with advanced solid tumors or NSCLC harboring NTRK1, 2, and 3 rearrangements. Hence, detection of NTRK2 translocations by Fluorescence in situ Hybridization (FISH) may be of diagnostic and therapeutic relevance.