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Novel approaches to protein measurement based on mass spectrometry are being developed that challenge more traditional methods. This review summarizes the emergence of mass spectrometry as a tool for clinical protein, peptide, and amino acid determination. Specific applications of mass spectrometry to the measurement of transferrin, transthyretin, glycated hemoglobin, and homocysteine will be discussed, as will the limitations of the technology, and future directions for clinical protein measurement.