The natural history of hepatitis C is highly variable from one infected individual to another. Once chronic infection is established, prognosis mainly depends on the amount and progression of liver fibrosis and the risk of developing cirrhosis. Liver biopsy, traditionally considered as the reference standard for staging of fibrosis, has been challenged over the past decade by the development of novel non-invasive methodologies. These methods rely on two distinct but complementary approaches: (1) a “biological” approach based on the levels of serum biomarkers of fibrosis, and (2) a “physical” approach based on the measurement of liver stiffness using transient elastography. The use of non-invasive methods to assess liver fibrosis in chronic hepatitis C has resulted in a significant decrease in the need for liver biopsy. However, these methods will likely not completely abolish the need for liver biopsy, and they should rather be employed as an integrated diagnostic algorithm with liver biopsy.