The overarching goal of our translational research program is to delineate the genetic predisposition and environmental contributors that affect the pathogenesis, and determine the outcomes of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). These are rare, progressive, liver diseases that diminish quality of life and shorten patients’ life expectancy in the absence of liver transplantation. PBC affects primarily women (~90%) and ursodeoxycholic acid is the only therapy that improves survival; yet, ~30% of patients do not respond to it and advance to end-stage liver disease. PSC is strongly associated with inflammatory bowel disease (~80%), medical therapy is lacking and patients have a high risk for developing colorectal and bile-duct cancer. We have developed bio-repositories from PBC and PSC patients, linked to clinical phenotypes with long-term follow-up, and longitudinal prospective questionnaire data. Our PBC studies have led to seminal observations including that cytotoxic T-lymphocyte-associated protein 4 and interleukin-12 immunoregulatory signaling axis are important in PBC pathogenesis. This effort has resulted in novel ongoing clinical trials to improve therapy for this disease. Currently, we are working to identify genetic variants that predict response to ursodeoxycholic acid therapy in PBC patients. Our PSC studies have contributed in the identification of several susceptibility loci of the disease. Presently, we execute studies to find the genetic loci that predispose to PSC outcome (i.e., progression to liver transplantation, development of colon or bile-duct cancer). In the era of precision medicine such discoveries will ultimately improve the medical care of patients with PBC or PSC.