Around 257 million people worldwide have chronic hepatitis B virus (HBV) infection, which leads to almost 1 million deaths per year from complications, mainly decompensated cirrhosis and hepatocellular carcinoma. The development of effective treatments for hepatitis C virus has led to hope for a cure for HBV. Current treatments for HBV infection include pegylated interferon-alfa, which is associated with modest efficacy and poor tolerability, or nucleoside analogues, which require lifelong administration and rarely achieve hepatitis B surface antigen (HBsAg) loss. Understanding the HBV lifecycle is essential to develop new approaches, since each step is a potential target for drug development. New direct-acting antivirals for HBV in development include entry inhibitors, capsid assembly modulators, and drugs targeting cccDNA or HBV RNA, and HBsAg secretion inhibitors. In this Review, we discuss potential targets and direct-acting antiviral approaches in development.