Because of its development marked by a long preclinical phase and the difficulties to screen patients, lung cancer is usually diagnosed at an advanced stage of disease, even in high-risk populations. The advent of new molecular tools, including proteomics, has promoted the study of the humoral response to cancer and has allowed the demonstration of the appearance of a large number of autoantibodies against tumor antigens in the serum of patients. In this article, we describe the different molecular approaches used to identify autoantibodies and immunogenic proteins and we present the different clinical studies applied to early detection of lung cancer. Early trials demonstrated the development of a humoral response several months before the first radiographic or clinical signs. Further studies are under evaluation and are intended to identify early forms of cancer in populations with high cancer risk. Many efforts are made in the implementation of robust and reproducible tests that could help to the emergence in the future of such biological tools in clinical practice.