Telbivudine was recently approved for the treatment of chronic hepatitis B. Phase III studies indicated its antiviral potency with 6- to 6.5-log copies/mL reductions in hepatitis B DNA levels at year 1, comparable to other potent agents such as entecavir or tenofovir. Genotypic resistance rates, however, reached 25% at year 2 in hepatitis B e-antigen positive subjects and 11% in hepatitis B e-antigen negative subjects, preventing it from becoming a preferred first-line drug for hepatitis B. Furthermore, its signature resistance mutation (a change from methionine to isoleucine at position 204 in the reverse transcriptase domain of the hepatitis B polymerase) also confers cross-resistance to entecavir, lamivudine, and emtricitabine. Telbivudine is well tolerated, with elevations in creatine phosphokinase being the most common abnormality observed in clinical trials. Most often, elevations were asymptomatic. Future research in hepatitis B will focus on the best ways to use existing therapies, including telbivudine, sequentially or in combination in order to maximize viral suppression and minimize the development of antiviral resistance.