Lamivudine is an effective first-line therapy for chronic hepatitis B virus (HBV) infection, accomplishing the goals of viral suppression, normalization of alanine aminotransferase (ALT) levels, histological improvement, and seroconversion. In the lamivudine clinical trials, up to 32% of patients positive for hepatitis B e antigen (HBeAg) lost HBeAg after 1 year of treatment, and approximately 18% achieved HBeAg seroconversion. ALT levels greater than five times the upper limit of normal increased the likelihood of HBeAg loss. The rates of seroconversion and resistance both increase with the length of treatment. In HBeAg-negative patients, two thirds showed response after 6 to 12 months of therapy, but this response diminished over time despite continued treatment, largely due to the emergence of resistance. Resistance is present in nearly 70% of patients at 5 years. Resistance reverses prior biochemical, virological, and histological gains and can lead to progressive liver failure. Careful patient selection is important, therefore, to maximize the potential for a treatment response under limited therapy.