Abstract: Analysis of blood samples from patients suffering from autoimmune diseases remains a mainstay in the clinic for initial diagnosis, prognostication, and clinical decision making. In particular, testing for the presence of serum autoantibodies has proved to be one of the most useful confirmatory assays for many different diseases. Recent genomic and transcript profiling studies have implicated certain cytokines, surface receptors, signaling pathways, and cell types in the pathogenesis of inflammatory diseases. The next obvious step is to delve into the much more complex level that follows the genome and transcriptome—the expressed proteome. This review focuses on several proteomics technologies being applied and/or developed by our laboratory for the study of autoimmunity, cancer, and cardiovascular disease, all of which are known to be associated with defects in immunity and inflammation. The findings of other participants in the recent Human Immunology Conference hosted by the Dana Foundation and the New York Academy of Sciences (May 17 & 18, 2005) are included. In particular, major pitfalls in the study of the human proteome are pointed out, and important areas for immediate investigation to move the field forward as rapidly as possible are proposed.