Injection drug use remains the predominant mode of transmission of hepatitis C virus (HCV) infection. Growing numbers of persons who have been chronically infected with HCV for 20 or more years are coming to medical attention and are at risk for serious complications of chronic infection, including cirrhosis and hepatocellular carcinoma. Factors linked with the development of advanced fibrosis and cirrhosis include age at infection, duration of infection, heavy alcohol use, coinfections with HIV or hepatitis B virus, and male sex. Emerging risk factors for disease progression include steatosis, insulin resistance (and factors associated with the metabolic syndrome), and host genetics.