The chimpanzee model has played a major role both before and after the discovery of hepatitis C virus (HCV) as the etiologic agent of non-A, non-B hepatitis (NANBH). Chimpanzees were essential to prove that NANBH was indeed an infectious disease caused by a transmissible agent, and provided an in vivo system for the biological amplification of the putative virus to obtain sufficient material for attempts at identification. It was from a chronically infected chimpanzee that a large amount of plasma was obtained for the molecular cloning of the HCV genome. The chimpanzee model has played a critical role not only in the initial discovery but also in the post-HCV era. Studies in chimpanzees were instrumental to investigate the host immune response elicited by HCV and to determine the natural history of hepatitis C. Finally, chimpanzees remain the only animal model to study the immunogenicity and efficacy of vaccine candidates against HCV. In this chapter, we review the role that nonhuman primate models have played before and after the discovery of the etiologic agent of NANBH. Furthermore, we discuss the utility of small-animal models that have been developed over the past 10 years for studies of HCV.