Cancer sera contain antibodies which react with a unique group of autologous cellular antigens called tumor-associated antigens (TAAs). Cancer has long been recognized as a multi-step process which involves not only genetic changes conferring growth advantage but also factors which disrupt regulation of growth and differentiation. It is possible that some of these factors could be identified and their functions evaluated with the aid of autoantibodies arising during tumorigenesis. The multi-factorial and multi-step nature in the molecular pathogenesis of human cancers must be taken into account in both the design and interpretation of studies to identify biomarkers which will be useful for early detection of cancer. Our recent studies suggest that the combination of antibodies against a group of TAAs might acquire higher sensitivity for diagnosis of cancer. It is conceivable that autoantibody profiles involving different panels or arrays of TAAs might be developed in the future and the results could be useful for cancer diagnosis.