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Hepatitis C virus (HCV) infection is one of the main causes of end-stage liver disease and indications for liver transplantation (LT) worldwide. HCV infection always recurs on the graft in patients who undergo LT with detectable serum HCV RNA, leading to cirrhosis in 20–30% within 5 years after transplantation. Achieving a sustained virological response (SVR) greatly improves patient and graft survival. Recently, the efficacy of therapy has radically changed and improved based on new direct acting antiviral agents (DAAs) without pegylated-interferon (PEG-IFN) and/or ribavirin (RBV), leading to SVR rates of more than 90% in transplanted patients. The safety profile in this population is also good, with limited drug–drug interactions. However, there are very few data on patients on the waiting list. Even when the results of combined DAAs are good (>80%), SVR rates are lower than in patients without cirrhosis. This review reports recent available data on the treatment of HCV infection in the transplant setting and discusses new dilemmas and challenges.