The 2012 edition of the NCCN guidelines recommends crizotinib as a first-line treatment option for patients with ALK-positive NSCLC. In recent years, EML4-ALK has become a new favorite in targeted therapy research. In NSCLC patients, the positive rate of ALK rearrangement is about 3% to 5%, and the odds of EML4-ALK fusion are high in patients with adenocarcinoma, never or little smoking, and ALK-positive patients are younger but have a poorer prognosis compared to ALK-negative NSCLC patients. Crizotinib is a dual blocker of ALK and c-MET genes or their variants. Two multicenter single-arm clinical trials showed significant therapeutic activity of crizotinib in patients with ALK-positive NSCLC. One was the PROFILE 1001 study part 2 extension cohort study, which included 119 patients, with an objective remission rate (ORR) of 61% and a median duration of remission of 48.1 weeks in the crizotinib group. Another study was PROFILE 1005, in which 136 patients with ALK-positive advanced NSCLC who had failed prior chemotherapy (93% of patients had been treated with at least 2 or more chemotherapy regimens) from 12 countries were treated with crizotinib. The results showed that patients had an ORR of 50% and a median duration of remission of 41.9 weeks. The most common adverse reactions (≥25%) observed in both studies were visual impairment, nausea, diarrhea, edema, and constipation. Based on the results of these two studies, the FDA approved crizotinib for the first-line treatment of locally advanced or metastatic ALK-positive NSCLC in August 2011. Is crizotinib available for second-line treatment? An ongoing randomized phase III clinical study (PROFILE1007) is currently comparing crizotinib with other second-line treatment options, and we look forward to the publication of the results. The addition of crizotinib to first-line therapy is undoubtedly a major breakthrough in targeted therapy for NSCLC patients, but despite the relatively high efficiency (>80%), patients who are effectively treated with crizotinib usually develop resistance after 1 year of treatment, so further research is needed to explore the mechanism of crizotinib resistance and how to overcome it.