Virological tools play a major role in the diagnosis of hepatitis C virus (HCV) infection and in ongoing decision-making based on the patient's virological response to therapy. Virological tools used to assess viral kinetics and viral genomics can also be applied to clinical and translational research, especially in studies aimed at understanding the mechanisms underlying HCV treatment failure. Viral kinetics studies are based on quantification of HCV RNA at prescribed intervals during treatment and mathematical modeling of HCV RNA dynamics. These studies require sensitive and specific HCV RNA assays with an extended dynamic range of quantification. Viral genomics methods are useful to correlate viral kinetics with the intrinsic genomic characteristics of the HCV infecting strain. The interpretation of results utilizing various viral genomics tools is difficult, however, and must include predictive structural and functional genomic analyses. These approaches will be particularly useful in studying the mechanisms of HCV treatment failure with new HCV inhibitors currently under development.