Background: Hepatitis C virus (HCV) infection is still one of the leading causes of chronic liver disease, with chronically infected making up approximately 1% of the global population. Of those infected, 70% (55-85%) will develop chronic HCV infection. Chronic HCV infection causes substantial morbidity and mortality, with complications including cirrhosis, end-stage liver disease, hepatocellular carcinoma, and eventually death. Objective: Therapeutic options for chronic HCV infection have evolved dramatically since 2014, with a translation from pegylated interferon and ribavirin (associated with suboptimal cure and high treatment-related toxicity) to oral direct- acting antiviral treatment. There are four classes of direct-acting antivirals which differ by their mechanism of action and therapeutic target. They are all pointed to proteins that form the cytoplasmic viral replication complex. Multiple studies have demonstrated that direct-acting antiviral therapy is extremely well tolerated, highly efficacious, with few side effects. Methods: We performed an indexed MEDLINE search with keywords regarding specific direct-acting antiviral regimes and their pharmacokinetics, drug-drug interactions, and metabolism in specific settings of pregnancy, lactation, liver cirrhosis, liver transplantation and HCC risk, kidney failure and kidney transplantation. Results: We present a comprehensive overview of specific direct-acting antiviral metabolism and drug-drug interaction issues in different settings. Conclusion: Despite its complex pharmacokinetics and the possibility of drug-drug interactions, direct-acting antivirals are highly efficacious in providing viral clearance, which is an obvious advantage compared to possible interactions or side effects. They should be administered cautiously in patients with other comorbidities, and with tight control of immunosuppressive therapy.