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Proteins are the center of all biochemical reactions in living organisms. Proteins need to be present at the right time, in the right place, with the correct concentration and have the right shape to carry their designated function. Protein homeostasis is when all proteins in the proteome are in functional balance, and such balance is maintained by synthesis, folding, and degradation machinery. When protein homeostasis is lost, organisms start to age and develop diseases. To truly unveil disease mechanisms and provide more efficient means for treatment and prevention, we need a holistic understanding of the mechanism of protein homeostasis. Currently, most biomarker studies focus on the quantity aspect of the proteome. The quality aspect has been neglected because of the difficulties in measuring quality in vivo with cellular context retained. This work first proposes a kinetic model of protein homeostasis, which can provide a holistic view, including both quantity and quality aspects, as well as monitor the complex protein interactions. Using mass spectrometry, the model quantifies the quality of proteome by linking the concentration of protein, mRNA, and the rate protein synthesis, folding, unfolding, misfolding, refolding, degradation of the correctly folded protein, and degradation of protein aggregation. We then applied the ideas within the kinetic model of protein homeostasis to study several proteins in human blood serum. We reviewed the current known mechanism of transthyretin mediated amyloidosis and proposed a study approach that can measure the quality difference between different transthyretin's mutation stages, as well as monitor if the transthyretin amyloidosis has been developed at the early stage. We also used mass-spectrometry to quantify the surface accessibility differences in human serum albumin (HSA) between patients with and without rheumatoid arthritis (RA). We found certain residues are less reactive in the RA group, indicating a structural change in HSA. Such structural changes, possibly caused by ligand binding, stabilized HSA and explained the heat denature curve shift we observed. In the end, we introduced a novel assay, Iodination Protein Stability Assay (IPSA). IPSA is used to quantify protein quality by measuring protein folding stability. We applied IPSA to human serum, and it is the first in situ study, to our best knowledge, that measure the protein folding stability of proteins from human serum. We confirmed that IPSA is sensitive to measuring the differences in protein folding stability between transferrin's different iron-binding states. Together, this dissertation conveys the importance of adding quality aspects to current quantity-focused research in curing diseases and improving the quality of human life.