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Search terms included \u2018DAAs\u2019, \u2018safety\u2019, and \u2018tolerability\u2019.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>While DAAs are remarkably well tolerated, they are accompanied by unique AEs. Simeprevir, an NS3\/4A protease inhibitor, has been known, albeit infrequently, to cause mild hyperbilirubinemia and photosensitivity reactions; and paritaprevir boosted with ritonavir causes bilirubin and ALT elevations. Asunaprevir, another protease inhibitor, infrequently causes elevated transaminase levels. NS5A and NS5B inhibitors are well tolerated, although sofosbuvir is contraindicated in patients with severe renal impairment. Ribavirin co\u2010administered in certain treatment regimens has been associated with cough, rash and haemolytic anaemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>With the impending reality of a more tolerable interferon\u2010sparing regimen, the future of DAA therapy offers shorter treatment duration, simplified disease management, and a patient\u2010centred regimen. With advantages come drawbacks, including development of resistance to therapy and accessibility to this expensive treatment. DAA therapy continues to advance at a brisk pace with a promising trend for higher tolerability, even in difficult\u2010to\u2010treat subgroups such as those with cirrhosis, nonresponders to prior therapy, and transplant recipients. Subgroup\u2010specific contraindications and safety\u2010related limitations are active areas of research. 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