The field of mass spectrometry-based proteomics has been transformed over the last decade due to advances in technology, sample preparation, bioinformatics, and computational tools. While this has led to a dramatic increase in research related to biomarker discovery, the promise of finding a significant number of new biomarkers has not yet materialized. Current proteomic technology is able to detect and analyze extremely small amounts of proteins (picomole to attomole level), but has difficulty detecting and quantifying proteins present at 2- to 3-orders of magnitude lower than the more abundant proteins. This is referred to as the dynamic range problem. Normal biological fluids used for biomarker discovery, such as plasma or urine, contain a small number of proteins present at much higher amounts than the remaining proteins. For example, in the plasma, albumin and immunoglobulins are present at milligrams per milliliter, while proteins of interest for biomarker discovery may be present at micrograms to picograms per ml. This has led us to investigate the microparticle subproteome which has a high likelihood of containing potential biomarkers. While this subproteome makes up less than 0.01% of the total plasma proteome, it is rich in proteins altered under a variety of pathological conditions.