Even though available data about ALK TKI in the next-line setting can be summarized in an unambiguous empirical algorithm (Figure 2), and the approval status of these drugs does not depend on the detection of any specific molecular alteration in rebiopsies, profiling of ALK+ NSCLC at progression is still very desirable, mostly for one main reason: the identification of potentially actionable off-target resistance mechanisms. The gene discussed is ALK; the disease is non-small cell lung carcinoma.