: rearrangements are present in 2-7% of non-small cell lung cancer (NSCLC) cases, where the fusion is the most frequent. Rearrangement of with other fusion partners occurs only in ≈5% of NSCLC ALK-positive. These patients have benefit from inhibitors and currently, there are three generations of drugs as standard of care. The first generation ALK inhibitor crizotinib is approved in the front line setting for the treatment of advanced NSCLC; unfortunately, these tumors may eventually develop resistance to this molecule. The Second-generation A inhibitors, ceritinib, alectinib and brigatinib, are approved for patients recently diagnosed or in relapse. The third-generation inhibitor lorlatininb is approved for patients who have developed resistance to any ALK inhibitor.: In this review, an unstructured search in Pubmed and SCOPUS was conducted. We summarized the mechanisms of resistance to inhibitors and its consequences in the treatment-decision making in advanced or metastatic NSCLC after failure to a first-line inhibitor.: Currently, there are a growing number of options of therapeutic agents against ALK+ NSCLC (approved and in development); however, adequate selection and sequencing of agents is crucial to deal with the tumor evolution.