In recent years, significant advances have been achieved both in the development of animal- and tissue-culture models for HCV. Among all the new systems, the small animal model based on transgenic mice with chimeric mouse-human livers and the replicon system will presumably have the most profound impact on future HCV research. Yet, in spite of this progress, much more work will be required to optimizse both systems. In case of the mouse model, breeding homozygous Alb-uPa animals is difficult because of the toxicity of the transgene, and the transplantation of primary human hepatocytes into mice a few days after birth is technically challenging. These are immunodeficient, and, therefore, it will be desirable to furnish them with components of the human immune system in order to expand the applicability of this in vivo model to questions related to pathogenesis. Advances in cryopreservation techniques are urgently needed, moreover, as this would improve the availability of primary hepatocytes and in turn also the accessibility of this small animal model. As regards the replicon system, a number of open questions remain that will hopefully be answered by future research. Why, for instance, has replication in cell culture so far been achieved only with genotype 1b isolates, whereas an isolate with proven infectivity derived from genotype 1a failed to replicate in Huh-7 cells? And why can replicons so far be propagated only in this particular cell line? Is this attributable to the lack of certain inhibitory factors, or the presence of specific activators? What are the mechanisms underlying cell-culture adaptation. and what determines whether a certain Huh-7 cell replicates HCV RNA more efficiently? Finally, the replicon system may also lead the way to the development of systems for efficient virus production in cell culture, and ultimately also a permissive cell line. These developments would at last allow us to model the complete viral life cycle, something researchers have been struggling with ever since the first identification of HCV.