Globally, hepatic diseases are an important cause of mortality and morbidity. Harnessing RNA interference (RNAi) to silence pathology-causing genes specifically offers exciting possibilities for improvement of treatment. Nevertheless achieving efficient and safe delivery of RNAi activators remains an important objective before this gene silencing approach realizes its full therapeutic potential. Several viral and non viral vectors (NVVs) are being developed for hepatotropic delivery of synthetic and expressed RNAi activators. Each has advantages and disadvantages that are suited to particular disease conditions. Amongst the viral vectors, recombinant adeno-associated viruses and PEG-modified helper dependent adenoviruses show promise for situations that require intermediate to long term expression of RNAi activators. Recombinant lentiviruses have not been used extensively as hepatotropic RNAi vectors, but are likely to find application where lasting therapeutic silencing is required. NVVs are a particularly important class of vector and are effective for delivery of synthetic RNAi activators to the liver. Preclinical investigations using RNAi-mediated gene silencing to counter persistent hepatitis B virus, hepatitis C virus, hepatocellular carcinoma, hypercholesterolemia and cirrhosis are discussed in this review. Although obstacles remain, vigorous research has given impetus to the field and RNAi-based treatment of liver diseases is likely to become a reality in the near future.