Abstract Purpose of Review Current treatments for chronic hepatitis B (CHB) are associated with low rates of cure. Functional cure has been accepted as a viable treatment end point in CHB. There have been substantial advances in the field of RNA interference (RNAi) therapeutics across a wide range of specialties, and the clinical pipeline now encompasses CHB. This review will highlight some of the challenges in therapeutic development, the data for RNAi in CHB, and future directions for the field. Recent Findings Early phase clinical trials have reported good safety data for RNAi therapies in CHB and demonstrated significant reductions in quantitative HBsAg levels (qHBsAg). Animal models however suggest that in HBeAg-negative individuals, HBsAg may be derived from hepatitis B DNA integrated into the host genome, which cannot be targeted by current RNAi therapies, and may prove to be a limitation. Preliminary data is being presented from combination therapy, which may result in more robust reductions in qHBsAg; however, trials are in the early stages of recruitment. Summary Despite promising data that RNAi may be an effective therapeutic strategy in CHB, it is unlikely to be in the form of monotherapy. The goal for the community will be to find the right combination of RNAi therapy with other antiviral or immunomodulatory agents, to achieve functional cure with a cessation of therapy. Early phase clinical trials are continuing to recruit, and data from combination studies will provide a “pivot point” in determining whether RNAi therapies can provide a backbone to finite duration and curative CHB regimens.