Treatment of chronic hepatitis C virus infection has substantially improved following the advent of direct acting antiviral (DAA) agents. Although the first generation protease inhibitors telaprevir and boceprevir improved sustained viral response (SVR) rates, adverse events remain severe and immature termination of the therapy is frequent; however, intensive dose modification has improved completion and SVR rates. Interferon-free DAA combination therapies, such as asunaprevir and daclatasvir dual therapy are under development and promise higher SVR rates with fewer adverse events. Resistance monitoring and modification of DAA therapy based on pre-existing or de novo resistance variants should be considered. Future therapies are expected to have pan-genotypic activity with shorter duration and improved tolerability, even among cirrhotic and liver transplant patients.