The US Food and Drug Administration has recently approved a number of new direct-acting antiviral agents for the treatment of chronic hepatitis C virus that have significantly increased the likelihood of a virological cure. These agents are highly effective but present a substantial risk for a host of clinically relevant drug-drug interactions. These interactions must be considered both when starting and stopping any medication, including over-the-counter medications and herbal supplements. These drug-drug interactions can increase the risk of toxicity or decrease the likelihood of treatment response. Knowledge of these interactions is paramount in optimizing the success of antiviral therapy. Conclusion: In this review we summarize the available data regarding drug-drug interactions for direct-acting antiviral agents, the interactions being the most clinically relevant that are currently known; this review is intended to serve as a clinician's guide to understanding and managing these complex interactions. (HEPATOLOGY 2016;63:634-643) D irect acting antiviral agents (DAAs) have transformed the management of hepatitis C viral (HCV) infection. Virological cure rates of >90% are routinely achievable across HCV genotypes and irrespective of the presence of cirrhosis and prior non-DAA treatment history. Although highly effective and well tolerated, DAAs present unique and important potential for drug-drug interactions that must be considered before, during, and after initiation of DAAbased therapy. This review summarizes the available data regarding the most clinically relevant drug-drug interactions for DAAs with the goal of optimizing pharmacotherapeutic outcomes.