Spontaneous autoantibody responses against tumor-associated antigens have been detected in all types of cancer analyzed so far. Recent studies have shown that cancer-associated autoantibodies can be found in the serum of patients even several years before the clinical diagnosis. Furthermore, they may at least partially reflect the antigenic profile of cancer and the balance of immune cell subsets in the tumor microenvironment. Therefore, cancer associatedautoantibodies represent attractive biomarkers for the development of non-invasive serological tests for the diagnosis or early detection of cancer, prognosis of survival and prediction of the clinical benefit of immunotherapy. Still, the frequency of responses against each particular antigen is generally low and the autoantibody repertoire is highly heterogeneous and overlapping with that elicited by viral infections and autoimmune disorders, hence precluding the clinical use of single autoantibody biomarkers. This can, however, be overcome by analyzing the autoantibody responses to multiple antigens simultaneously. In this review, we discuss the diagnostic relevance of the recently identified cancer-associated autoantibody signatures and the challenges in the development of clinically applicable biomarker assays. In addition, the putative functional role and the significance of IgG subclasses in the anti-tumor immune response and their prognostic value are discussed.