Hepatitis C follows a variable course with some patients developing progressive liver fibrosis, cirrhosis and hepatocellular carcinoma, while others have minimal or no significant liver disease after decades of infection. Studies have identified both host and viral factors associated with disease progression. The importance of general factors such as age at infection, gender, immune status and alcohol consumption has long been recognized; however recently, polymorphisms in a wide array of genes have also been shown to be associated with progressive fibrosis. How specific viral proteins may contribute to disease progression has also been studied. This review highlights what is currently known about the factors associated with progressive liver injury in patients with hepatitis C. A greater understanding of the determinants of disease progression will hopefully lead to improved utilization of existing treatments and ultimately may aid in identification of new therapeutic targets. (Hepatology 2006;43;S194–S206.)