Fifteen years after the discovery of the hepatitis C virus, a substantial amount of information has been learned about the natural history of infection. Testing for viral nucleic acid made it possible to accurately diagnose chronic infection and provided a more precise estimate of the overall frequency of viral persistence. Although cirrhosis and hepatocellular carcinoma can arise in persons with chronic hepatitis C, these outcomes do not always occur. The cirrhosis risk is greater in those who are infected at older ages, those who drink >50 g of alcohol each day, and persons coinfected with HIV. However, much of the person-to-person variability in progression of chronic hepatitis C remains unexplained. The ability to detect persons at highest risk of progression remains incomplete and represents an important future challenge in the understanding of the natural history of hepatitis C.