The production of autoantibodies against tumour-derived proteins has been observed in the most, if not all cancer patients therefore they seem to be very attractive biomarkers for the diagnosis or early detection of cancer. Moreover, even if they by themselves have a minor role in the anti-tumour immune response, the autoantibody profile likely reflects the repertoire of activated CD4+ T cells, presumably, including both, the helper cells and the regulatory T cells. Hence, they may turn out to be valuable biomarkers for monitoring patients response to immunotherapy. So far, their clinical utility has been hampered by the low frequency against each antigen, the inability to differentiate between different types of cancer, large interindividual variations in autoantibody repertoires and ambiguous biological and clinical significance. At least partially these limitations could be overcome by applying high-throughput proteomic techniques to cancer serology that allows definition of a comprehensive set of antigens in each type of cancer and analysing the whole autoantibody profiles in patients sera. In this review we aim to give an insight into the recent advances in applying various proteomic approaches, including phage display-based SEREX, SERPA, MAPPing and protein microarrays for the identification of tumour-associated antigens and autoantibody profiling, and discuss the relevance of autoantibodies for the early detection of cancer and monitoring patients response to therapy.