Research on Hepatitis C Virus inhibitors has dramatically increased during the past few years. Actually, several classes of anti-HCV drugs, including NS3/4A protease inhibitors, NS5B polymerase inhibitors, NS4B protein to RNA binding inhibitors, and multifunctional viral protein NS5A inhibitors, are in different stages of development. The RNA dependent HCV polymerase is considered an irreplaceable target for future HCV therapy on account of a high degree of conservation across the six HCV genotypes, and agents targeting the active site, such as ribonucleoside analogs, may be particularly advantageous having a high barrier to resistance. The purpose of this review is to present highlights of recent developments in the synthesis of anti-HCV ribonucleosides and to discuss the limitations posed by resistance and drug toxicity.