Comprehensive, robust, and inexpensive clinical tools are needed to monitor human health and disease. In this review, we propose how a standardized, high-performance antibody testing platform directed against a broad panel of antigenic targets could fulfill an important niche in personalized medicine. The panel is envisioned to encompass a defined set of diverse protein antigens known to be associated with cancer, autoimmune diseases, and infectious diseases, including proteins derived from bacterial pathogens and the human virome. Early detection of immunoreactivity to various antigens and autoantigens, before symptoms develop, might inform about evolving autoimmunity, cancer progression, or other health problems and provide unique opportunities for early, more effective clinical intervention. Furthermore, antibody detection for known pathogenic infectious agents, as well as cataloging host responses to seemingly non-pathogenic microbes, could offer treatment options and/or potentially represent novel, early biomarkers for different diseases and immune status. The overarching goal would be to exploit changes in an individual's comprehensive antibody profile longitudinally as a personalized indicator for disease prediction, diagnosis, and monitoring.