There is an important need to find relevant biomarkers that show high sensitivity and specificity for early diagnosis and prognosis of many cancers. To day, immunoproteomics is a relatively new concept in the field of proteomics and an increasingly powerful technology in the hunt for new and novel diagnostic and prognostic biomarkers. For cancer diagnostic, it is important that circulating autoantibodies reflect a molecular imprint of those antigens (lowabundance) that are specifically related to tumor. Identification of tumor-associated antigens and their cognate autoantibodies is a promising strategy for the discovery of relevant biomarkers. Importantly, sera fromtumor patients contain tumor specific antibodies directly against antigenic proteins. Also, autoantibodies are highly stable compared to many other serum proteins, they seem ideal to be implemented in clinical diagnostic assays for the detection of antigen-associated diseases. To facilitate autoantibody discovery, approaches that allow the simultaneous identification ofmultiple autoantibodies are preferred. During the past few years, proteomic approaches, including SEREX and SERPA, have been the dominant strategies used to identify tumor-associated antigens and their cognate autoantibodies. In this review, we will outline the advances applications of immunoproteomics for the discovery and analysis of clinically relevant protein targets and discuss their merits in clinical applications of the most common cancers.