The production of tumor-specific antibodies in melanoma from patient-derived B cells in the peripheral blood and tumors has been reported and has yielded a few antibodies of the IgM and IgG class [31, 32, 33, 34] . In the past, such studies have been limited by poor EBV transformation efficiency of human B cells, low production of immunoglobulin, evaluation of few patients, and lack of effective, reproducible methods to rapidly screen for tumorspecific antibodies. To address some of these limitations, we took advantage of recent advances in growing and immortalizing memory B cells in culture [35, 36] , increased the number of patients evaluated, and developed a novel screening tool to specifically detect tumor-reactive antibodies against cell surface antigens on melanoma cells. Our approach entails culture of patient-derived circulating B cells and screening of the antibodies they secrete for their reactivity and specificity to melanoma cells versus melanocytes. Our strategy does not screen for antibodies against known antigens or evaluate antibodies secreted or sequestered in the serum at discrete times, but rather uniquely, the aim here is to monitor tumor cell-reactive IgG antibodies produced by B cell cultures, elucidating the breadth of the longterm mature B cell repertoire recognizing melanoma antigens expressed on the surface of cancer cells.