Chronic infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide and is the most frequent indication for liver transplantation in the United States and Europe. It is estimated that up to four million persons in the United States have been infected with HCV, and analysis of existing data on the current prevalence and duration of infection projects a substantial burden from the late manifestations of this disease over the next 10 to 20 years, including liver failure and hepatocellular carcinoma. Hepatitis C has been a regular topic of previous issues of Clinics in Liver Disease based on the rapid pace of new knowledge regarding this disease. The goal of this issue is to update selected areas of new or enhanced knowledge regarding hepatitis C. There have been significant scientific and clinical advances in the understanding of the virology, natural history and diagnosis of chronic hepatitis C, which are featured in the first part of this issue of Clinics in Liver Disease. Dr. Jeffrey Glenn reviews how better understanding of the basic virology of HCV has the potential to lead to novel therapies. Dr. Pawlotsky describes the currently available tools to diagnose and monitor HCV infection during therapy. Study of the natural history of chronic hepatitis C has always been a challenge because of the long duration of infection and variability in the rate of progression; Dr. Seeff updates current information of this challenging topic. There is also recent recognition of the frequency and impact of hepatic steatosis on the natural history and response to therapy in patients with chronic hepatitis C, which is reviewed by Dr. McHutchison.