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Gainor, Dardaei, and colleagues performed a molecular and functional analysis of repeat biopsies from patients with ALK-rearranged non–small cell lung cancer who developed ALK inhibitor resistance. ALK resistance mutations were more common after treatment with second-generation ALK inhibitors compared to treatment with the first-generation ALK inhibitor crizotinib, and each ALK inhibitor exhibited a specific spectrum of ALK resistance mutations. Identification of epithelial–mesenchymal transition (EMT) in a subset of second-generation ALK inhibitor–resistant biopsies suggested that EMT may contribute to second-generation ALK inhibitor resistance. The third-generation ALK inhibitor lorlatinib exhibited potency against single and compound ALK resistance mutations induced by second-generation ALK inhibitors. Together, these results describe the molecular mechanisms of resistance to first- and second-generation ALK inhibitors and highlight the importance of longitudinal sampling. For details, please see the article by Gainor, Dardaei, and colleagues on page 1118.