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Crizotinib now is accepted as the standard first-line treatment of ALK-rearranged lung adenocarcinomas. To overcome the problem of crizotinib resistance, second-generation ALK inhibitors are in development. The aim of this review is to give an overview on the mechanisms behind crizotinib resistance and on the preclinical background and clinical development of these compounds.Based on phase I/II data, ceritinib has gained accelerated FDA approval for the treatment of crizotinib-resistant ALK-rearranged lung cancer. The clinical development of alectinib has already reached phase III. With AP26113, ASP3026, TSR-011, X-396 and different heat shock protein 90 inhibitors, several other compounds led to promising early trial results. The toxicity profile of these drugs seems manageable, although side-effects still require attention and optimized supportive care.Second-generation ALK inhibitors have arrived as part of our daily clinical practice. Challenges for the future will be to find the optimal place for these new drugs within the treatment algorithms. To reach this goal, careful trial design with special emphasis on genetically defined, homogeneous patient populations is imperative.