Chronic hepatitis B virus infection, a major cause of end-stage liver disease and hepatocellular carcinoma, is a worldwide health concern. While the past two decades have brought major advances in the availability of treatments to help delay or prevent these outcomes, treatment of chronic hepatitis B remains a serious challenge, not least due to the ability of the virus to remain in hepatocyte nuclei as a source of potential reactivation-hence the term chronic hepatitis B infection. This article reviews the current treatments available and suggests a framework for a rational approach to managing the disease.