Hepatitis B virus (HBV) infection is a global human health problem, with an estimated 350 million people having chronic hepatitis B (CHB) infection worldwide. The majority of infections acquired during adulthood are resolved without intervention; however, infections acquired at birth or during early childhood have a 90% chance of progressing to CHB, leading to a host of adverse effects on the liver, including cirrhosis and cancer. CHB is currently treated with a combination of cytokines and/or nucleoside/nucleotide analogues; however, adverse side effects to cytokine therapy and the selection of resistance mutations to nucleoside analogues often abrogate the efficacy of treatment. The recent discovery that small interfering RNA and microRNA are active in mammalian cells suggests it might be possible to supplement existing HBV therapies with small RNA-based therapeutic(s).