Reports of tumor-specific antibodies in the sera of melanoma patients date back over forty years [25] and have so far provided valuable insight into immune responses to cancer. Serological studies of individuals with melanoma have shown that patients expressing certain tumor-associated antigens have antibodies against these antigens, conversely, patients without the antibodies also lack the corresponding tumor antigens [26] . These studies have been restricted to few antibodies in sera against known tumor-associated antigens. Serological studies reported IgG antibodies recognizing intracellular melanocyte and melanomaassociated antigens such as tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2, and melanoma-associated glycoprotein antigen family (gp100/pmel17) in patients with melanoma. Serumresident antibodies to some of these antigens were enhanced following polyvalent melanoma cell vaccine immunization in patients with melanoma, suggesting that melanoma-associated antigens may be immunogenic and that humoral responses to melanocyte and melanoma antigens may constitute potential targets for immunotherapy [27] . New antigens, such as the NY-ESO-1, with restricted expression in normal tissues and wide distribution in various cancers including melanoma have been discovered using serological analysis of recombinant cDNA expression libraries (SEREX) techniques tested against tumor mRNA and autologous patient sera [28] . SEREX studies from human melanomas [29] and from one cell line [30] have led to the discovery of the human testis antigen HOM-MEL-40. Many of these antigens are primarily intracellular, making them less attractive targets as monoclonal antibodies. Furthermore, serological screens may also be limited by the temporal dynamics of sera antibodies. Evaluating the reactivity of antibodies secreted by circulating B cells may therefore provide additional insight to serological evaluations by interrogating the long-term memory anti-tumor systemic mature humoral response to cancer.