Publisher Summary Autoimmunity (autoantibodies as well as autoreactive T cells) is often associated with tumor development. The sooner cancer is diagnosed, the better the therapeutic outcome. However, an early diagnosis is a problem with many kinds of tumors, namely, lung, pancreas, gallbladder, and colon cancer. Therefore, there is a need for parameters which are specific for tumors and are detectable in preclinical stages. Autoantibodies (AAb) directed against self antigens is classified into two main categories: natural occurring autoantibodies (NOA) and non natural AAb. NOA have different biological effects ranging from enhancement of, to surveillance of tumor development. The induction and presence of nonnatural autoantibodies in tumor patients is associated with aberrant or overexpression of the autoantigenic targets in the tumor. The detection of such AAb is important to find new markers for the improvement of diagnosis and prognosis of tumors. Proteins encoded by oncogenes and tumor suppressor genes are involved in the control of cell growth and differentiation and, if inappropriately expressed or mutated, in the genesis of tumors. The chapter describes the presence of AAb against oncoproteins, the tumor suppressor proteins p53, and proteins involved in cell-cycle regulation/progression and mitosis. Such immune responses are of special interest in the early diagnosis and therapy of cancer. The chapter discusses about autoantibodies against cancer/testis class of tumor antigens (CTAs). Onconeural antigens (ONA) are normally restricted to the nervous system but are aberrantly expressed in a number of tumors by gene activation or derepression, or post-transcriptional regulatory mechanisms. AAb against ONA detects neuronal nuclear antigens, cytoplasmic antigens of Purkinje, and synaptic or retinal proteins. The chapter briefly describes the detection of disease-specific AAb in cancer patients without or before the development of autoimmune disease.