Variants of hepatitis B virus (HBV), hepatitis C virus (HCV) and of the hepatitis Delta virus (HDV) have been identified in patients both with acute and chronic infections. In the HBV DNA genome, naturally occurring mutations have been found in all viral genes, most notably in the genes coding for the structural envelope and nucleocapsid proteins. In the HCV RNA genome, the regions coding for the structural envelope proteins 1 and 2 as well as the 3’-contiguous nonstructural region 1 were found to be hypervariable. Viral variants may be associated with a specific clinical course of the infection, e.g. acute-fulminant or chronic hepatitis. Specific mutations may reduce viral clearance by immune mechanisms (‘immune escape’) or response to antiviral therapy (‘therapy escape’). Furthermore, mutations of envelope epitopes can lead to viral variants which are not recognized or neutralized by antibodies to wild-type virus, resulting in ‘diagnosis escape’ or ‘vaccine escape’. The exact contribution, however, of specific mutations to the pathogenesis and natural course of HBV, HCV or HDV infection, including the development of hepatocellular carcinoma, remains to be established.