It is now widely accepted that 85% or more of individuals with acute hepatitis C virus (HCV) infection progress to chronic hepatitis, and chronic hepatitis C is a known risk factor for cirrhosis and hepatocellular carcinoma (HCC). However, there has been much controversy about the inevitability of developing cirrhosis and HCC and the time frames in which they are likely to occur. Natural history studies have provided varying estimates of the risk of progression in chronic hepatitis C. Part of this variation may be a result of viral-specific, host, and/or environmental factors, but much of it undoubtedly is a result of the difficulties of doing natural history studies in this disease: acute onset is rarely identified, chronic infection is often asymptomatic, and the duration of disease is prolonged. Three types of studies--prospective, retrospective, and retrospective-prospective (nonconcurrent prospective)--have attempted to determine the clinical outcomes of chronic HCV infection and have provided widely varying estimates. The combined population data indicate that the disease progresses slowly over approximately 30 years, on average. Approximately 20% of infected individuals will progress to fibrosis and cirrhosis. Of these, approximately 20% will progress to HCC. The likelihood of progression appears to be independent of genotype or viral load but increases with alcohol intake, male sex, age over 40 years at infection, and coinfection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV). Results of ongoing nonconcurrent studies are needed to determine disease progression in the third, fourth, and fifth decades of infection and to better define the factors that affect progression.