Several direct-acting antiviral agents (DAAs) have marketing authorization in Europe and in the USA and have changed the landscape of hepatitis C treatment: each DAA has its own metabolism and drug–drug interactions (DDIs), and managing them is a challenge. To compile the pharmacokinetics and DDI data of the new DAA and to provide a guide for management of DDI. An indexed MEDLINE search was conducted using the keywords: DAA, hepatitis C, simeprevir, daclatasvir, ledipasvir, sofosbuvir, 3D regimen (paritaprevir/ritonavir, ombitasvir, dasabuvir), DDI and pharmacokinetics. Data were also collected from hepatology, and infectious disease and clinical pharmacology conferences abstracts. Food can play a role in the absorption of DAAs. Most of the interactions are linked to metabolism (cytochrome P450-3 A4 [CYP3A4]) or hepatic and/or intestinal transporters (organic anion-transporting polypeptide and P-glycoprotein [P-gp]). To a lesser extent other pathways can be involved such as breast cancer resistance protein transporter or UDP-glucuronosyltransferase metabolism. DDI are more likely to occur with 3D regimen, daclatasvir, simeprevir and ledipasvir, as they are all both substrates and inhibitors of P-gp and/or CYP3A4, than with sofosbuvir. They can increase concentrations of coadministered drugs and their concentrations may be influenced by P-gp or CYP3A4 inducers or inhibitors. Overdosage or low dosage can be encountered with potent inducers or inhibitors of CYP3A4 or drugs with a narrow therapeutic range. The key to interpret DDI data is a good understanding of the pharmacokinetic profiles of the drugs involved. Their ability to inhibit CYP450-3A4 and transporters (hepatic and/or intestinal) can have significant clinical consequences.