The hepatitis C virus (HCV) is a positive-strand RNA virus that belongs to the genus Hepacivirus of the family Flaviviridae. The development of a system to propagate this human pathogen in cell culture took more than a decade since the first molecular cloning of the HCV genome. It was a stepwise achievement that began with the construction of the first functional HCV genome with proven in vivo infectivity. It was then followed by the establishment of subgenomic replicons that self-amplify in cultured human hepatoma cells, and culminated in the generation of infectious HCV upon transfection of these cells with a particular molecular HCV clone designated JFH-1. In this review, we will summarize the development and current state of molecular HCV clones and discuss the prospects and implications of the most recent achievements. (c) 2007 Elsevier B.V. All rights reserved.