The therapeutic landscape of lung cancer has evolved tremendously over the past 10 years with the discovery of oncogenic drivers constitutively activated by mutation, translocation or fusion. An activating EGFR mutation or ALK rearrangement is present in around 15% of Caucasian patients with non-small cell lung cancer (NSCLC), with targeted therapy constituting the basis of upfront treatment for these patients. Additional potential drivers in NSCLC patients have been found in adenocarcinomas, including mutations in KRAS, BRAF, HER2, and fusions involving the RET, and ROS oncogenes. Many of these molecular abnormalities are found more frequently in never-smokers, relaunching a clinical interest in this patient population. Approximately 25% of all lung cancers are not attributable to tobacco, and the proportion of never-smokers with lung cancer has been increasing over time [1]. Lung cancer in never-smokers is thus regarded as a distinct disease entity with a variable tumorigenic pattern, clinicopathology, and natural history. Two major issues are addressed in the head-to-head papers of the Biocast prospective study: the first describes data on risk factors for NSCLC in never-smokers, and the second concerns the molecular profile of NSCLC in never-smokers.