There are at least 4 million cases of hepatitis C virus (HCV) infection in the United States (overall prevalence 1.8%, with many of these patients unaware of their infection) and 170 million worldwide. The consequences of this virus account for 10,000 deaths every year in the United States. HCV is the primary reason for liver transplantation in this country. Most new cases are now acquired through the use of illegal injection drugs (68%) or potentially sexual transmission (18%). Although the incidence of HCV infection has dropped sharply since the early 1990s because of improved blood-supply screening, the infections that were acquired from the 1960s to the 1980s are likely to dramatically increase the morbidity, mortality, and costs of HCV disease over the next 2 decades. A proportion of these individuals with long-term HCV infection will develop cirrhosis, decompensated liver disease, or hepatocellular carcinoma (HCC). These increases in HCV-related end-stage liver disease and HCC will have significant implications for clinicians and pharmacists in managed care settings. This article reviews the virology, serology, epidemiology, natural history, and the current and projected future disease burden of HCV in the United States.