Recent advances in the development of agents that act specifically to inhibit hepatitis C virus (HCV) are set to fundamentally change the way that patients will be treated. New directly acting anti-HCV agents such as protease and polymerase inhibitors will initially be added to standard of care with pegylated interferon-alpha and ribavirin. However, future therapy is likely to constitute combinations of agents which act at distinct stages of viral replication and have differing resistance profiles. While directly acting anti-HCV agents will undoubtedly improve treatment outcomes, the introduction of combination therapy may not be without complications in some patient groups. HIV-positive patients who are receiving antiretrovirals (ARVs) are relatively highly represented among those with HCV infection, and are at high risk of drug-drug interactions (DDIs). As combination anti-HCV treatment gradually evolves to resemble anti-HIV therapy, it is essential to consider the increased potential for DDIs in patients receiving combination anti-HCV therapy, and particularly in HCV/HIV-co-infected individuals. Therapeutic drug monitoring is likely to play a role in the clinical management of such interactions.