Searching for ALK rearrangements has now become mandatory for the treatment of patients with advanced non–small cell lung cancer with anti-ALK-targeted therapy. The fluorescence in situ hybridization test is considered the “gold standard” to diagnose ALK-rearranged tumors. Nevertheless, some technical pitfalls may cause false-positive signals mimicking ALK rearrangements. In this technical article, we point out the importance of taking into account both histopathologic and ALK immunohistochemical features to interpret ALK fluorescence in situ hybridization analyses in inflammatory and necrotic tumors. This confrontation is crucial to avoid misdiagnosis and inappropriate therapeutic management.