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Antiviral drug discovery aims to identify novel agents that inhibit viral replication or reduce expression of key pathogenic viral proteins while minimizing adverse effects. Target-based screening has been employed extensively to identify compounds targeting both viral and host proteins. While phenotypic screening has successfully identified antiviral compounds, determining each compound's target is challenging. Approximately 240 million individuals worldwide are chronically infected with hepatitis B virus (HBV), and more than 650 000 people die per year from HBV-associated liver diseases. The hallmarks of chronic HBV infection are high viral load (HBV DNA) and higher levels of non-infectious particles containing the tolerogenic viral S antigen (HBsAg). The current standard of care effectively reduces viremia, but rarely results in a functional cure, defined as sustained HBsAg loss. Recently, a novel, potent, small-molecule inhibitor of HBV gene expression (RG7834) was discovered from a phenotypic screen focused on identifying HBsAg production inhibitors. Target identification efforts led to the discovery of the non-canonical poly(A) RNA polymerases PAPD5 and PAPD7, which are required for HBV RNA stabilization, and are effectively antagonized by RG7834. Thus, we highlight the powerful approach of phenotypic screening for identifying novel antiviral drugs and unraveling key biological mechanisms important for the viral lifecycle.