The hepatitis C virus (HCV) lifecycle appears to be confined to the cytoplasm of hepatocytes. This has translated into the ability to produce sustained virological responses (SVRs) in a substantial proportion of HCV-infected people. Lower treatment responses and higher relapse rates in co-infection may be a consequence of HCV more frequently infecting difficult-to-access reservoirs such as peripheral blood mononuclear cells. However, the durability of sustained response appears to be minimally altered in co-infection. In light of these modest SVRs, and accelerated hepatic fibrosis progression among co-infected people, strategies to slow disease progression take on greater importance. In this context, histological response becomes an important endpoint in co-infection. Multicentre randomized trials of PEG-IFN and ribavirin demonstrate that assessment of histological responses either at the conclusion of therapy or 24 weeks after completion of therapy identify a number of patients who experience improvements in histological activity index in the absence of virological clearance. The prognostic value of serum markers of fibrosis in co-infection has not been validated, but this represents a particularly important area for development in co-infection in light of the probable need for more intensive histological sampling. Eventually, it is anticipated that genotype-phenotype correlations will permit selection of optimized antiviral regimens once virus specific enzymatic inhibitors have been approved.