Publisher Summary Patients with cancer frequently develop antinuclear auto-antibodies, however, the mechanisms by which autoimmunity develops and the significance of these antibodies in these patients is uncertain. The chapter describes experiments to show the association between the auto-immunity and cancer. The experiment hypothesize that the proteins involved in tumorigenesis comprise a class of autoantigens that is more generally recognized in a groups of patients. The chapter discusses various reasons for considering this hypothesis. Lung cancer is considered as a model system for associating antinuclear antibodies and oncogenesis. The chapter lists down various reasons for this. The chapter describes a new approach, SEREX, to identify autoantibodies associated with lung cancer. The studies from this approach suggest that autoimmunity is a prominent feature of lung cancer and molecular characterization of nuclear autoantigens may lead to the discovery of proteins with diagnostic and prognostic value. The chapter compares the autoimmune response in lung cancer and the systemic autoimmune diseases. A parallel can be drawn between the systemic autoimmune diseases and cancer in relation to the antinuclear antibodies observed in both conditions. In both, cellular proteins become antigenic targets of humoral response.