Ribavirin is an old broad-spectrum antiviral that is highly effective when used in combination with interferon-alpha and also as part of triple therapies containing new inhibitors of the hepatitis C virus (HCV) non-structural (NS)3/4 protease or HCV NS5B polymerase for the treatment of patients with chronic hepatitis C. However, the molecular mechanisms by which ribavirin enhances early and sustained virological response rates during interferon-based antiviral HCV therapy are still unknown. Several mechanisms including (i) immunomodulatory properties, (ii) inhibition of the inosine monophosphate dehydrogenase, (iii) direct inhibition of the HCV-encoded NS5B RNA polymerase, (iv) induction of lethal mutagenesis and (v) modulation of interferon-stimulated gene expression are currently proposed. Here, we discuss recent advances from in vitro data and their importance for the situation in patients with chronic hepatitis C. Furthermore, theoretical aspects from mathematical modelling of ribavirin action in chronic hepatitis C are reviewed.