The treatment of non–small cell lung cancer (NSCLC) has been revolutionized by the discovery of genetic driver mutations and associated targeted therapies. Anaplastic lymphoma kinase ( ALK) mutations are present in about 5% of NSCLC cases, and treatment with the first-generation ALK inhibitor crizotinib has shown better progression-free survival (PFS) and response rate compared to traditional chemotherapy. However, eventually, ALK-mutated NSCLC develops resistance to treatment with crizotinib, and second-generation ALK inhibitors such as ceritinib, brigatinib, and alectinib have been shown to be effective in the second-line setting after progression on crizotinib. In the second-line setting, alectinib showed an objective response rate (ORR) of 45% and PFS of 8 to 12 months. Brigatinib showed an ORR of 45% to 54% with a PFS of 9.2 to 12.9 months in the second-line setting. A more recent trial compared alectinib to crizotinib in the treatment-naive setting and showed a significant PFS benefit to treatment with alectinib. The second-generation ALK inihibitors brigatinib and alectinib offer new options for the treatment of ALK mutation–positive NSCLC.