Hepatitis C virus (HCV) exhibits a narrow host range and a specific tissue tropism. Mice expressing major entry receptors for HCV permit viral entry, and therefore the species tropism of HCV infection is considered to be reliant on the expression of the entry receptors. However, HCV receptor candidates are expressed and replication of HCV-RNA can be detected in several nonhepatic cell lines, suggesting that nonhepatic cells are also susceptible to HCV infection. Recently it was shown that the exogenous expression of a liver-specific microRNA, miR-122, facilitated the efficient replication of HCV not only in hepatic cell lines, including Hep3B and HepG2 cells, but also in nonhepatic cell lines, including Hec1B and HEK-293T cells, suggesting that miR-122 is required for the efficient replication of HCV in cultured cells. However, no infectious particle was detected in the nonhepatic cell lines, in spite of the efficient replication of HCV-RNA. In the nonhepatic cells, only small numbers of lipid droplets and low levels of very-low-density lipoprotein-associated proteins were observed compared with findings in the hepatic cell lines, suggesting that functional lipid metabolism participates in the assembly of HCV. Taken together, these findings indicate that miR-122 and functional lipid metabolism are involved in the tissue tropism of HCV infection. In this review, we would like to focus on the role of miR-122 and lipid metabolism in the cell tropism of HCV.