Interferons (IFNs) are an integral part of the immune system, which upon stimulation results in recruitment of cytokines for viral clearance. IFNs have been characterized as potent antiviral agents that which can reduce viral titer and have been found to act as critical mediators for tumor regression in few cases. During the course of time Hepatitis C virus (HCV) has evolved and influence IFN efficiency through various pathways. Rapidly occurring amino acid substitutions in HCV's core protein, sequence homology with protein kinase (PKR), increased numbers of quasi-species and wild-type Interferon sensitivity determining region (ISDR) strains are linked with an inefficient response to IFN therapy. This article describes the pharmacodynamics of IFNs with an aim to decipher the possible involvement of HCV proteins in subverting these responses. We hereby discuss IFN-based therapies targeting the host and viral genetic factors, since they have a strong impact in determining the efficacy of an IFN in HCV infected host.