The heterogeneity of hepatitis B virus (HBV) is increasingly believed to play a role in viral persistence, pathogenesis, and the type of response to antiviral therapy. One of the best studied parts of the HBV genome is the C-gene which codes for the nucleocapsid protein (HBc) and the e-antigen (HBeAg). Here we attempt to review the recent data on the sequence heterogeneity of this region and its possible implications.