HCV infections are a major global health burden. After the identification of the virus in 1989, insights into viral replication and drug development have long been hampered by the lack of efficient cell culture models. Their establishment was an important prerequisite for the development of selective antivirals. This review describes the initial difficulties to achieve HCV replication in cell culture, finally leading to the establishment of subgenomic replicons and the infectious virus model (HCVcc). The review further summarizes the current state of HCV cell culture systems with respect to available virus isolates, engineered genomes, and cell types allowing efficient HCV propagation. Finally, we comment on how these cell culture models contributed to the development of directly acting antivirals.