Estimates of hepatitis C virus infection include 170 million people worldwide, who face increased risk of development of cirrhosis, liver failure, and hepatocellular carcinoma. Standard of care therapy with pegylated interferon and ribavirin is effective in just half of patients, is challenged by substantial treatment-related morbidity, and is prohibitively expensive in most parts of the world. New therapeutics for treatment and prevention are clearly needed. Development of effective therapies has been significantly hampered by difficulties in establishing in vitro and in vivo models of viral replication. This chapter reviews development, validation, and early application of a mouse model with a chimeric human liver.