Nucleoside analogues have been recently introduced in the management of chronic hepatitis B virus (HBV) infection. They mainly act by inhibition of HBV polymerase activity resulting in decrease of viral replication. They are administered orally, and most of them have an excellent tolerance and safety profile. Lamivudine is the only nucleoside analogue licensed for chronic hepatitis B. It has potent activity against HBV, and a 12-month course achieves clearance of hepatitis B e antigen (HBeAg) in 20-30% of HBeAg-positive patients and both biochemical and virological remission in more than 65-70% of HBeAg-negative chronic hepatitis B patients. Famciclovir and ganciclovir are less effective, whereas other nucleoside or nucleotide analogues, such as adefovir, entecavir, and emtricitabine, are currently under evaluation. Prolonged effective antiviral therapy is required for eradication of chronic HBV infection, but long-term treatment with nucleoside analogues has been found to be associated with progressively increasing rates of viral resistance because of emergence of resistant HBV mutant strains. Virological breakthroughs usually develop after the first 6 months of lamivudine monotherapy, and their rate ranges between 15% and 30% at 12 months and exceeds 50% after 3 yr of therapy. Resistant HBV mutant strains harbor point mutations in the HBV polymerase gene and predominantly in the well-conserved YMDD motif. Although resistant HBV strains may have impaired replication capacity compared with the wild HBV, their clinical significance has not been completely clarified yet. No significant biochemical or clinical event may develop in some cases, whereas severe biochemical breakthroughs with or without deterioration of liver function may develop in others. To date, there is no proven effective therapy for the resistant HBV mutant strains, although adefovir and entecavir seem to be interesting candidates.