There are now five nucleoside/nucleotide analogs approved for the treatment of chronic hepatitis B (CHB) including three agents approved in the United States and/or European Union in the past three years. Each of these drugs has demonstrated short-term benefits in patients including histologic improvement, HBeAg seroconversion, suppression of hepatitis B virus (HBV) DNA, and alanine aminotransferase (ALT) normalization. However, long-term therapy is required in most patients and the five approved agents differ with respect to resistance profile and ability to achieve complete antiviral suppression. Lamivudine was the first approved agent, but its use leads to frequent antiviral resistance. Adefovir dipivoxil has a superior first line resistance profile and is fully active against lamivudine-resistant HBV. Newer agents including tenofovir disoproxil fumarate, entecavir, and telbivudine offer greater potency than lamivudine and adefovir dipivoxil. However, telbivudine resistance rates are comparatively high and both telbivudine and entecavir have decreased efficacy against lamivudine-resistant HBV. Tenofovir disoproxil fumarate, the most recently approved nucleotide (2008 in the European Union, and United States), is highly potent in both treatment-naïve and treatment-experienced patients. Overall, this class of compounds presents the opportunity to achieve complete antiviral suppression in the majority of patients, at least in the short-term. The challenge is how to best use these drugs long-term to minimize antiviral resistance and maintain maximal antiviral suppression, which is anticipated to make the greatest impact on limiting advanced complications of CHB.