Chronic hepatitis C is highly heterogeneous in clinical presentation and outcomes. This heterogeneity is largely related to host factors that have been clearly proven to affect the severity and rapidity of disease progression. The most relevant factors that have been shown to accelerate progression to cirrhosis include age at infection, alcohol abuse and the metabolic syndrome with insulin resistance, obesity and hepatic steatosis. Co-infection with HIV and/or HBV also increases the risk of progression to cirrhosis and to hepatocellular carcinoma. Surprisingly enough, viral related factors appear as less important and neither the virus genotype and load have been found to exert a clear influence on disease severity and progression, although more data in this field, and particularly on the role of different viral proteins in causing cytopathic effects, are awaited and may change this view in the near future.