Famciclovir (FCV, the oral form of penciclovir, PCV) is a potent antiviral agent of hepatitis B virus (HBV) and is currently in phase III clinical trials. In this review, we examine the outcome of FCV treatment in preventing recurrent HBV in patients post transplantation. Resistance to FCV has now been documented in this setting, in which reduced sensitivity to FCV was associated with mutations upstream from the conserved ‘YMDD’ motif in the HBV polymerase gene. These mutations are in a region which has been designated as the B domain in RNA-dependent polymerases. To understand these mutations we have developed a model of the catalytic regions of the HBV polymerase and located mutations selected during antiviral treatment on this mo