Lung cancer is the leading cause of cancer death worldwide and it would be essential to have effective tools to diagnose the disease in its early stages, to identify individuals at highest risk of developing the disease, and to set personalised therapies. The effectiveness of screening for lung cancer with low-dose CT (LDCT) in heavy smokers was demonstrated, in terms of reduction of cause-specific mortality, in recently published data by the study National Lung ScreeningTrial (NLST). In Europe, the introduction of LDCT as screening in individuals at risk is the object of a debate until the results of European randomized trials, expected in 2015-2016, are published. One problem is the high rate of calls for investigations when there is a noncalcified nodule, and it is therefore essential to be able to more accurately identify malignant nodules. The development of specific biomarkers appears to offer promising prospects. Recent advances in genetics and genomics have led to a series of studies aimed at the identification of molecular markers for the diagnosis, the assessment of the risk of developing lung cancer, the molecular characterisation of the different stages of the disease and the personalisation of therapy. Subjects enrolled in trials evaluating LCDT as a test for early detection of lung cancer represent the ideal population in which to study a combined bioinstrumental approach of screening (molecular test and LDCT). This paper reports on the state of knowledge on the possible use of biomarkers in the early detection of lung cancer and molecular analysis conducted within the project ITALUNG, a randomized controlled trial to assess the effect on tumour-specific mortality of LDCT, which provided a collection of biological materials from the subjects enrolled.