All viral infections subvert the host immune response. Targeting the host mechanisms that are modulated by viral infection offers new avenues for antiviral drug development. Host ubiquitin and multiple ubiquitin-like modifiers (Ubls) are commonly altered by, or important for, viral infection. Protein modification by ubiquitin or Ubls contributes to numerous cellular processes, such as protein degradation, signal transduction, protein relocalization and pathogen-host interactions. This post-translational modification plays an essential role for viral life cycles and host antiviral mechanisms. Some Ubls, such as ISG15 and SUMO, have been shown to modulate virus infections and are potential targets for therapeutic manipulation. Hepatitis C virus (HCV) is a positive-stranded RNA virus that predominantly infects hepatocytes. Recent data suggest that ISG15 might be a potential drug target for anti-HCV therapy. Inhibition of ISG15 expression and/or ISG15 conjugation (ISGylation) provides a rationale for the design of new anti-HCV drugs.