Two of the key events in the viral life cycle of the hepatitis B virus (HBV) involve (1) generation from genomic DNA of the covalently closed circular DNA transcriptional template and (2) reverse transcription of the viral pregenomic RNA to form the HBV DNA genome. Because the virus employs reverse transcription to copy its genome, mutant viral genomes are found frequently. Particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antivirals), readily select out these escape mutants. The introduction of nucleoside/nucleotide analogue therapy has seen the emergence of drug resistance as the major factor limiting drug efficacy. The development of drug resistance is not unexpected if viral replication continues in the setting of ongoing treatment, especially monotherapy. Thus, prevention of resistance requires the adoption of strategies that effectively control virus replication.