The availability of a cell culture system is a critical prerequisite to study the replication cycle of a virus and to devise strategies for prophylactic and therapeutic interventions. Such a system depends on two elementary components: an infectable host cell supporting production of infectious virus progeny and a virus that is capable of replicating and assembling infectious particles in these cells. From a technical point of view this is relatively easy to achieve, but what if the virus does not replicate in cultured cells? There are several examples of medically very important viruses that cannot or can only poorly be propagated in cell culture, hepatitis C virus (HCV) being one prominent example. All attempts to culture this pathogen have been faced with major roadblocks that could be overcome only step-by-step. The most recent achievement is a virus production system that is based on the transfection of the human hepatoma cell line Huh-7 with genomic HCV RNA derived from a cloned viral genome (1). Although it was a major step forward, the system was in need of improvement because of limited virus yields and limited spread in cell culture. In a recent issue of PNAS, a study by Zhong et al.(2) showed that improvement can be achieved by using particularly permissive cells derived from the human hepatoma cell line Huh-7, yielding virus titers that are 50-fold higher and resulting in a more efficient spread of the infection. This is an important observation that broadens the scope of the HCV cell culture system (1) but at the same time raises the important question of what makes this system more efficient.