Abstract: Lung cancer is one of the most common malignant tumors in the world, more than 80% of whom are non-small cell lung cancer. Due to the insidious onset and lack of specific symptoms, most patients are diagnosed at an advanced stage, thus chemotherapy and molecular targeted therapy have become main treatment. The EML4-ALK fusion gene is one of the therapeutic targets for non-small cell lung cancer. It binds the intracellular tyrosine kinase domain to the extracellular ligand binding domain, resulting in the activation and expression of tyrosine kinase, toobtain carcinogenic effects. ALK fusion gene-positive lung cancer accounts for 3%-5% of non-small cell lung cancer and generally be in response to ALK tyrosine kinase inhibitors(TKIs). Crizotinib, as the first ALK inhibitors used in treatment of patients with advanced ALK-rearranged lung cancer, is well tolerated, benefits more than traditional chemotherapy, and improves objective response rateand quality of life. Ceritinib, alectinib, brigatinib, and lorlatinib also achieved considerable clinical benefit and were superior to crizotinib in clinical trials. The resistance of ALK inhibitors develops subsequently, including intrinsic resistance and acquired resistance, of which the most common mechanism is ALK-secondary mutations. The L1196 M mutation and the G1202 R mutation are the most common resistance mutations for crizotinib and second-generation ALK inhibitors, respectively. Currently, the first choice for drug resistance is the next-generation ALK inhibitors, and other treatments include combination with HSP90 inhibitor or pemetrexed. Fully understanding of the different mechanisms of resistance will help us to exploit personalized approaches overcoming resistance. This review aims to describe the key clinical trials of targeted therapy for ALK-positive advanced non-small cell lung cancer, and introduce advances in the diagnosis and treatments of drug resistance.