Advances in proteomics technologies, in particular the parallel development of highly sensitive mass spectrometers and accurate protein quantitation technologies, have allowed the detection and accurate measurement of low abundance proteins in bodily fluids and tissues. Furthermore, the application of these technologies in biomedical research has led to the identification of proteins and genes with expression patterns that change as a consequence of disease; detection and quantitation of these proteins and genes could provide valuable information for disease diagnosis and prognosis. For example, cell-surface protein expression can change in diseased cells. These proteins may then be secreted or shed from the cell surface; the levels of these proteins in blood or urine could provide valuable information for the diagnosis of disease and disease severity. The focus of this review is the methods by which proteomics-based technologies can be applied to characterize cell-surface proteins and to measure changes to expression levels in diseased states; the review also discusses the soluble counterparts of these surface proteins in the blood; these proteins could be important diagnostic and/or prognostic indicators of disease.