Lung cancer is the most common cancer worldwide and has high rates of mortality. The major risk factor associated with this disease is tobacco smoke, but approximately 10%–25% of all lung cancer cases occur in patients who have never smoked. Data suggest that lung cancer in never-smokers has a different molecular profile, tumour microenvironment and epidemiology than that in smokers. Several risk factors have been associated with its occurrence, and the possibility of inherited predisposition is becoming clearer. A better understanding of this disease is essential for the future development of personalised screening, diagnosis and treatment approaches, with consequent reduction of mortality. In this review, we discuss historical studies of lung cancer in never-smokers and the currently available evidence of inherited predisposition to this disease.