In this chapter, we describe the workflow of mass spectrometry (MS)-based proteomics with a focus on shotgun proteomics. We illustrate how MS-based proteomics can be applied to study liver pathophysiology using protein expression profiling, characterization of post-translational modifications (PTMs) and protein-protein interactions (PPIs). The publications on serum or plasma proteomics in the study of liver diseases during the years 2012 to 2017 are reviewed. We analyze the proportions of studies with regard to different kinds of liver disease and different proteomics workflows applied. Remarkably, outdated proteomics techniques were still being used in recent years and even account for a large proportion of the reviewed literature. The effort spent in different liver diseases is largely skewed to hepatocellular carcinoma and hepatic viral infection while a relatively small proportion focused on non-alcoholic fatty liver disease (NAFLD), which is the most prevalent liver disease worldwide. Finally, we describe plasma proteome profiling, a novel approach for biomarker discovery studies, and how this applies to liver diseases.