The worldwide prevalence of hepatitis C virus (HCV) infection and important health consequences associated with the chronic state of the disease, have become a serious health problem worldwide. To date, no vaccine is available to prevent this disease, and no specific antiviral agent directed against this dangerous human pathogen is at hand. The gold-standard treatment, based on interferon alone or in combination with ribavirin, has limited success, due to several side effects which, often, lead to therapy discontinuation. Thus, the treatment of chronic HCV infection is an urgent and yet unmet medical need. With the recent advances in the knowledge of HCV genome and replication, and the availability of crystal structures of the virally encoded enzymes, the NS5B RNA-dependent RNA-polymerase has emerged as an ideal target for the development of new, potent anti-HCV agents for the control of the disease. In this review, we will outline some of the criteria at the bases of targeted-drug design, and discuss some successful approaches towards the discovery of small molecule inhibitors against this non-structural viral enzyme