Alcohol-associated hepatitis (AH) and Hepatitis C virus (HCV) infection can cause mortality due to chronic liver injury, and may also progress to liver cancer. Little is known at the molecular level about the differences and similarities of AH and HCV, particularly in the role of the immune system during the development of hepatic injury. The overarching goal of my thesis is to understand the underlying biological mechanisms for AH and HCV. This will facilitate the identification and evaluation of genomic factors as both predictors of risk and as therapeutic targets in these liver diseases.This dissertation utilized biospecimens and data obtained from our collaboration with the Southern California Alcoholic Hepatitis Consortium (SCAHC) for Chapter 1 and 2, and also included eligible participants from three additional nation-wide consortia for Chapter 3. All participants had detailed clinical and phenotypic data, as well as various types of sequencing data, including bulk RNA sequencing, single-cell RNA sequencing, and whole exome sequencing data. This multi-centered and multi-ethnic approach provided a large case and control population with extensive phenotypic data and sequencing data, which allowed for powerful analyses and robust results. In Chapter 1, bulk RNA sequencing was utilized to discover biomarkers and determine biological mechanisms from gene expression data in both liver tissue and peripheral blood mononuclear cell samples, by comparing participants with viral hepatitis, alcohol-associated hepatitis, and healthy controls. Chapter 2 aimed to identify disease-critical inflammation markers and characterize peripheral immune profiles of AH at a cellular resolution using single-cell RNA sequencing. These studies have direct implications on the pathogenesis and prognosis of AH, and also may pave the way for liquid biopsy methods. Finally, Chapter 3 involved association testing with whole exome sequencing data from participants with AH versus heavy alcohol drinkers without liver disease, to identify rare variants for AH susceptibility, which could ultimately support the development of early interventions and improve patient care. Overall, this dissertation has provided significant contributions to the understanding of viral and alcohol-associated hepatitis and may facilitate future precise and personalized approaches for detection, diagnosis, and therapeutic target discovery.