ALK (anaplastic lymphoma kinase) rearrangements in non-small-cell lung cancer (NSCLC) have an estimated prevalence of 4-8%. ALK fusion proteins undergo ligand-independent dimerization and result in constitutive activation of the ALK tyrosine kinase. Tyrosine-kinase inhibitors that target the kinase activity of ALK have been found to have significant antiproliferative and proapoptotic effects. Although crizotinib treatment in ALK rearrangement-positive patients yields a pronounced clinical improvement, almost all patients eventually develop drug resistance. Ceritinib and alectinib are the new generation of ALK inhibitors, which overcome crizotinib resistance arising from ALK mutations or amplification. Other resistant mechanisms, such as activation of alternative pathways, remain to be discovered and validated. Further development of treatment strategy will improve the clinical outcome of patients with ALK-positive advanced NSCLC.