Genetic insight into the pathogenesis of lung cancer has paved the way for a new era in its treatment. Recently, anaplastic lymphoma kinase (ALK) has been identified as exerting a potent transforming effect through genetic rearrangement in patients with lung cancer. Preclinical and single-arm phase I studies have shown that patients with ALK-rearranged non-small cell lung cancer (NSCLC) can be successfully treated with crizotinib. Furthermore, a phase III randomized study indicated that crizotinib is superior to standard chemotherapy in the treatment of patients with NSCLC harboring the ALK rearrangement who had received 1 previous platinum-based chemotherapy. Despite the excellent efficacy of crizotinib in patients with ALK-positive (ALK(+)) lung cancer, resistance mechanisms--such as secondary mutations in the ALK gene, the activation of other oncogenes, and so on--have been identified as conferring resistance to crizotinib. Second-generation ALK inhibitors, such as alectinib and ceritinib, have been shown to be effective not only in crizotinib-naive patients but also in those resistant to crizotinib. Therefore, although some agents specifically targeting ALK have been developed and their efficacy has been documented, how ALK inhibitors should be administered in the setting of ALK-rearranged NSCLC remains to be fully elucidated. Can second-generation ALK inhibitors replace crizotinib? Is crizotinib just a first-generation ALK inhibitor? Is the sequential use of crizotinib and second-generation ALK inhibitors the best method? In this article, we review the preclinical and clinical results regarding crizotinib and second-generation ALK inhibitors, as well as the resistance mechanisms, and discuss the best methods for treating patients with ALK(+) NSCLC.