In 2016, the US Food and Drug Administration issued a warning about the risk of hepatitis B virus (HBV) reactivation in some patients receiving direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection. HBV reactivation can occur soon after the start of DAA therapy; thus, monitoring liver enzymes during DAA therapy is important in patients at risk. The clinical outcomes of HBV reactivation in this patient population may resemble the outcomes seen in immunosuppressed patients receiving chemotherapy. Each drug combination regimen has demonstrated risk for HBV reactivation and, therefore, contains a black box warning stating that all HCV-infected patients pending treatment should be tested for evidence of current or prior infection with HBV before initiating treatment. Both the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver guidelines have been updated accordingly.