Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus replication. In HBeAg-positive and HBeAg-negative lamivudine-naïve patients with chronic hepatitis B (CHB), treatment with ETV at a dose of 0.5 mg daily is associated with a more potent viral suppression, a higher rate of biochemical remission and a greater improvement of liver histology compared to Lamivudine (LAM). After 3 years of ETV treatment, the majority of patients (94%) may achieve serum HBV DNA levels undetectable by sensitive PCR assays. ETV treatment of patients with LAM-resistant HBV mutants requires a higher daily dose of 1 mg yet, potent HBV suppression at 3 years is achieved only in 40% of them while the cumulative rate of genotypic HBV resistance increases from 6% in the first year to >30% in year 3. ETV resistance of HBV is rare in lamivudine-naïve patients with a reported rate of <1% after three years of treatment. In conclusion, ETV is a very potent anti-HBV drug with a high genetic barrier to resistance, highly effective in lamivudine-naïve CHB patients and most promising for their long-term treatment but not very suitable for CHB patients harboring LAM–resistant HBV mutants.