Due to the intimate relationship between liver and kidney disease in hepatitis C virus (HCV) infection, treatment options for HCV-positive patients at any stage of chronic kidney disease (CKD) are essential. The availability of second-generation, direct-acting antiviral (DAA) combinations has allowed for the advent of interferon-sparing treatment regimens with shorter durations and minimal side effects. While many of the second-generation DAAs are principally metabolized by the hepatic system, dosing in severe renal impairment (creatinine clearance [CrCl] <30 mL/min) or dialysis has remained questionable due to limited experience. New evidence regarding the use of these agents in renal impairment continues to become available, as real-world experience with these treatment regimens is reported. Simeprevir, ledipasvir, paritaprevir, ombitasvir, dasabuvir, and daclatasvir have data to suggest safety in end-stage renal disease. While safety and efficacy with sofosbuvir remains uncertain, data are now available to support utilizing a dose adjustment when glomerular filtration rates are <30 mL/min. Upcoming regimens grazoprevir/elbasvir and daclatasvir/asunaprevir/beclavubir may provide further options for patients with advanced kidney disease, and ongoing studies will continue to provide guidance for this unique patient population. This article will review the currently available literature, including the newest emerging evidence, on the use of second-generation DAAs in CKD stages 3 to 5 and dialysis.