Abstract: Lung cancer is the most common malignant tumor worldwide, meanwhile the first cause of cancer-related deaths currently. Fortunately targeted therapy have dramatically reduced lung cancer-related mortality. As part of the genotype that displays significant association with non-small cell lung carcinoma (NSCLC), the anaplastic lymphoma kinase (ALK) gene has been developed three generations of anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs). Each generation of ALK-TKIs exhibits wider coverage of target sites and stronger tissue penetration ability than the previous. Despite considerable effort made through ALK-TKIs, drug resistance cannot be avoid. With increasing application of multiple ALK inhibitors and combined treatment regimens, new drug resistance mutations, compound mutations, and other mechanisms underlying drug resistance have been reported. Simultaneously, new markers for early diagnosis as well as predicting prognosis have also been identified. In order to get better understanding of drug resistance mechanisms and improved methods to detect NSCLC, the treatment become personalized based on genetic information certainly. It is hoped that newly discovered means to overcome drug resistance will place NSCLC in the category of chronic diseases near future. This review summarizes the research studies on ALK gene, drug resistance mechanisms and treatment strategies progress of targeted therapy, availability of diagnostic and prognostic markers to provide novel insights for the clinical management of ALK positive NSCLC patients.