Hepatitis B virus (HBV) chronically infects >250 million people and kills nearly a million annually, and current antivirals cannot clear the infection or adequately suppress disease. The virus replicates by reverse transcription, and the dominant antiviral drugs are nucleos(t)ide analogs that target the viral reverse transcriptase. We are developing antivirals targeting the other essential viral enzymatic activity, the ribonuclease H (RNaseH). HBV RNaseH inhibitors with efficacies in the low micromolar to nanomolar range against viral replication in culture have been identified in the α-hydroxytropolone and hydroxyimide chemotypes. Here, we review the promise of RNaseH inhibitors, their current structure-activity relationships, and challenges to optimizing the inhibitors into leads for clinical assessment.