A high rate of mutation sets a strong foundation for the development of resistance to antiviral drugs. However, the ubiquitous presence of drug resistance mutations in the HBV population does not explain variations in the rate and specific types of drug resistance among patients. These variations can be explained by consideration of coevolution among individual sites in the HBV genome, viral variants and subpopulations, as well as coevolution between the entire intrahost HBV population and the host. The concept of coevolution offers a more complete framework for understanding drug resistance.