The hepatitis C virus (HCV) is a global health issue with no vaccine available and limited clinical treatment options. Like other obligate parasites, HCV requires host cellular components of an infected individual to propagate. These host-virus interactions during HCV infection are complex and dynamic and involve the hijacking of host cell environments, enzymes and pathways. Understanding this unique molecular biosystem has the potential to yield new and exciting strategies for therapeutic intervention. Advances in genomics and proteomics have opened up new possibilities for the rapid measurement of global changes at the transcriptional and translational levels during infection. However, these techniques only yield snapshots of host-virus interactions during HCV infection. Other new methods that involve the imaging of biomolecular interactions during HCV infection are required to identify key interactions that may be transient and dynamic. Herein we highlight systems biology based strategies that have helped to identify key host-virus interactions during HCV replication and infection. Novel biophysical tools are also highlighted for identification and visualization of activities and interactions between HCV and its host hepatocyte. As some of these methods mature, we expect them to pave the way forward for further exploration of this complex biosystem and elucidation of mechanisms for HCV pathogenesis and carcinogenesis.