Inversions in the short arm of chromosome 2 [inv(2)(p21p23)] have been frequently detected in non-small cell lung cancer (NSCLC) and lead to the formation of EML4-ALK fusion transcripts. A few reports also identified these fusion transcripts in breast, gastric, and colorectal cancers. The fusion genes comprise variably truncated N-terminal portions of the EML4 gene and the intracellular signaling domain of the receptor tyrosine kinase ALK (anaplastic lymphoma receptor tyrosine kinase, a.k.a. CD246). It was found that EML4 mediates ligand-independent dimerization of ALK, resulting in constitutive kinase activity. EML4-ALK was shown to possess transforming activity in vitro and in vivo. The EML4-ALK fusion transcript is found in about 5% of NSCLC, predominantly adenocarcinomas, and is considered to be mutually exclusive to EGFR or KRAS mutations. The detection of the inversion by Fluorescence in situ Hybridization might represent a valuable tool to identify a subpopulation of NSCLC likely to respond to ALK kinase targeting therapies.