This review addresses the concepts, limitations and perspectives for the application of peptidomics science and technologies to discover putative biomarkers in blood specimens. Peptidomics can be defined as the comprehensive multiplex analysis of endogenous peptides contained within a biological sample under defined conditions to describe the multitude of native peptides in a biological compartment. In addition to the discovery of disease associated biomarkers, an emerging field in peptidomics is the analysis of peptides to describe in vivo effects of protease inhibitors. The development and application of peptidomics technologies represent an arena of biomarker research that has the potential for adding significant clinical value.