Individuals who have been exposed to lung carcinogenics are concerned by their greater risk of developing lung cancer, thus consult physicians with the expectation of undergoing screening tests. Controversy remains as to which screening procedures should be assessed. Previous studies of sputum cytology and chest X-rays showed no benefits in lung cancer mortality reduction. Screening of high risk individuals through computerized tomography scan appeared promising, but this radiological technique suffers from low specificity. Currently, the differential diagnosis is mainly based on additional imaging techniques, particularly positron emission tomography, which is expensive, and also shows limitations in terms of sensitivity and specificity. Therefore, purely morphological criteria seem to be insufficient to distinguish lung cancer at early stages from benign nodules with sufficient confidence, and false positives undergoing surgical resection seem to occur frequently. A molecular approach to the diagnosis of lung cancer through the analysis of biomarkers obtained by non invasive means could greatly improve the specificity of imaging procedures. Extremely sensitive mass spectrometric techniques are available to detect molecular alterations in accessible media, which characterise lung cancer at early stages, thereby reducing the rate of false positives, expected to be very out without a sound application of confirmatory diagnostic tests.