In this review, we examine the pharmacokinetics and clin-ically relevant drug interactions of the newer generation direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C, specifically sofosbuvir/velpatasvir (Epclusa?), sofosbuvir/velpatasvir/voxilaprevir (Vosevi?), glecaprevir/pibrentasvir (Maviret?), and elbasvir/grazoprevir (Zepat-ier?). We searched MEDLINE (1948-January 2020), Embase (1964-January 2020), Google, and GoogleScholar using the terms pharmacokinetics, drug interaction, drug metabolism, sofosbuvir, velpatasvir, Epclusa, voxilaprevir, Vosevi, glecap-revir, pibrentasvir, Maviret, elbasvir, grazoprevir, and Zepat-ier, from inception to January 13, 2020. The search was limited to randomized controlled trials, in vitro studies, pro-spective and retrospective human studies, drug monographs, abstracts, and conference proceedings. All relevant published literature on pharmacokinetic and pharmacodynamic interac-tions involving DAAs were reviewed and the data extracted. Numerous clinically relevant drug-drug interactions (DDIs) were identified with the newer generation DAAs and com-monly prescribed drugs. NS3/4A protease inhibitors are more likely to be involved in DDIs, followed by NS5A inhibitors and NS5B polymerase inhibitor. The majority of clinically relevant DDIs are predictable, according to known pharmacokinetic, pharmacodynamics, and physicochemical properties of DAAs;however, in select cases, unpredictable DDIs do occur. As expected, many drug interactions exist between newer generation DAAs and commonly prescribed medications. While the majority of clinically relevant interactions are pre-dictable, many require therapeutic dose adjustment or careful selection of non-interacting drugs. In select cases, severe and unpredictable drug interactions can occur. Clinicians should consult hepatitis C virus pharmacotherapy experts and terti-ary drug interaction resources when initiating DAA therapy in patients taking other medications.