Anaplastic lymphoma kinase (ALK) rearrangements (ALK-Rs) have been identified in 3–7% of all non-small-cell lung cancers (NSCLCs) and represent an important molecular target for NSCLC treatment. The authors discuss the role of ALK-Rs in the prediction of clinical–pathological features of NSCLCs and the technical problems related to their determination in specimens. The authors also describe the preclinical and clinical results derived from the use of ALK inhibitors. ALK-R is generally detected in patients with specific clinical–pathological features: never-smokers, young males, adenocarcinoma histotype and EGF receptor/KRAS wild-type. The diagnosis of ALK-R remains a challenge, implicating the need of a careful filtering of patients. NSCLC patients harboring ALK-R have shown sensitivity to ALK inhibitors even if their activity is limited at the time by the occurrence of mechanisms of resistance. The authors summarize the strategies that in the future could overcome these mechanisms of escape.