The study of the humoral response to infectious diseases and chronic diseases, such as cancer, is important for many reasons, including understanding the host response to disease, identification of protective antigens, vaccine development, and discovery of biomarkers for early diagnosis. During the past decade, proteomic approaches, such as serological proteome analysis (SERPA), have been used to identify the repertoire of immunoreactive proteins in various diseases. In this chapter, we provide an outline of the SERPA approach, using the analysis of sera from mice vaccinated with a live attenuated tularemia vaccine as an example.