Variants of hepatitis B, C, and delta virus have been identified in patients both with acute and chronic infections. In the hepatitis B virus 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 hepatitis C virus genome, the regions coding for the structural envelope proteins E1 and E2, as well as the 3'-contiguous non-structural region NS1, 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 ('vaccine escape' and 'immune escape'), response to antiviral therapy ('therapy escape'), as well as detection ('diagnosis escape'). The exact contribution, however, of specific mutations to the pathogenesis and natural course of hepatitis B, C, or delta virus infection, including hepatocellular carcinoma development, and the response to antiviral treatment remains to be established.