Hepatitis C virus (HCV) infected patients often take multiple co-medications to treat adverse events related to HCV therapy, or to manage other co-morbidities. Drug-drug interactions associated with this polypharmacy are relatively new to the field of HCV pharmacotherapy. With the advent of the direct-acting antivirals telaprevir and boceprevir, which are both substrates and inhibitors of the cytochrome P450 (CYP) 3A iso-enzyme, knowledge and awareness of drug-drug interactions have become a cornerstone in the evaluation of patients starting and continuing HCV combination therapy. In our opinion, an overview of conducted drug-drug interaction studies and a list of contra-indicated medications is not enough for the clinical management of these drug-drug interactions. Knowledge of pharmacokinetic profiles and concentration-effect relationships is key for the interpretation of these data, and insight how to manage these interactions (e.g., dose adjustments, safe alternatives and therapeutic drug monitoring) is of equal importance. This review provides a practical overview of the safe and effective management of these clinical challenges.