Serological analysis of recombinant complementary deoxyribonucleic acid (cDNA) expression libraries (SEREX) is a powerful approach to identify immunogenic cancer-associated proteins using antibodies that are naturally present in the serum of cancer patients. This technique involves the screening of a relevant cDNA expression library with patient serum that has been cleaned to remove any antibodies that may recognize bacterial and/or viral proteins. Once antigens have been identified and their reactivity has been confirmed with a second round of screening, the gene encoding the protein can be sequenced and identified. Antigens can then be screened with a panel of allogenic sera from other patients and control individuals. This identifies disease-specific antigens, which may be useful diagnostic markers or, alternatively, targets for immunotherapy. This chapter describes the SEREX methodology in full.