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Liver cancer, especially hepatocellular carcinoma (HCC), is one of the most common tumors worldwide. The majority of people with HCC will die within 1 year of its detection. The high case–fatality rate can, in part, be attributed to a lack of diagnostic methods that enable the early detection of liver cancer. Hence, there is a need for further understanding of tumor biology and host response mechanisms so that new diagnostic and therapeutic tools can be developed. There has been a growing interest in using serum anti-tumor-associated antigen (TAA) antibodies as serological cancer biomarkers. This interest stems from the notion that these anti-TAA antibodies are ‘sensors’ or ‘reporters’ of molecular events associated with tumorigenesis. The persistence and stability of autoantibodies in the serum of cancer patients is an advantage over other potential markers, including the TAAs themselves, some of which are released by tumors but rapidly degrade or are cleared after circulating in the serum for a limited time. Furthermore, the widespread availability of methods and reagents to detect serum autoantibodies facilitates their characterization in cancer patients and assay development. The hypothesis is that ‘customized’ TAA arrays constitute promising and powerful tools for enhancing the serological anti-TAA antibody detection of cancer. The present review will focus on the recent advances in our studies primarily associated with the idea and possibility that autoantibodies to TAAs can be used as biomarkers in immunodiagnosis of HCC and other solid tumors.