Modern gene profiling techniques have allowed in recent years considerable progresses in the knowledge of molecular alterations in the context of non-small cell lung cancer (NSCLC). In some cases, these alterations have been recognized as having a pathogenic role and targeted therapies capable of inhibiting tumor proliferation by selective and specific blocking of the enzymatic activity of the related abnormal proteins have been developed. This has made it possible to improve the effectiveness of the treatments by minimizing toxicity. Today it is essential to apply Comprehensive Genomic Profiling methods also in clinical practice, in order to allow the best treatment available for each patient, possibly also in the context of clinical trials. Below we report the clinical history of a patient with advanced stage adenocarcinoma of the lung with molecular diagnosis of RET fusion, treated with pralsetinib with excellent clinical and radiological response and good tolerability. This clinical case emphasizes the importance of the broader molecular profiling in patients with advanced NSCLC (especially for non-squamous histology) from the diagnosis before starting first-line treatment.