Hepatitis C virus (HCV) is one of the major causative agents inducing the development of hepatocellular carcinoma. The underlying mechanism of HCV pathogenesis, however, is largely un-known. Recent reports have implicated specific HCV proteins in persistent HCV infection, reduction of interferon sensitivity, and the modulation of cell proliferation, including alterations in apoptotic responses. However, the roles of these viral proteins remain controversial, because of conflicting results. Thus, it remains necessary to elucidate the precise molecular mechanisms through which the viral proteins influence cell growth and pathogenesis. In this review, after briefly describing what is known about the roles of the HCV proteins, in particular HCV core protein (core), in the modulation of cellular functions, we propose a novel molecular mechanism of the core in modulating gene expression via activation of nuclear hormone receptors.