Liver is the vital organ for synthesis of proteins whose concentration in blood reflects liver dysfunction. Variations in protein domain can generate clinically significant biomarkers. Biomarker pipeline includes discovery of candidates, qualification, verification, assay optimization, and validation. Advances in proteomic approach can discover protein biomarker candidates based on “up-or-down” regulation or fold change in expression which is correlated with disease state. Despite numerous biomarker candidates been discovered, only few are useful in clinical practice which indicates the need for well-established validation regimen. Hence, the main purpose of this review is to understand the protein biomarker development and pitfalls. Companion diagnostics provide insights into potential cost-effective diagnosis for chronic liver disease.