(i) CTLs with low functional avidity rarely select for escape variants, particularly with broad cross-recognition of mutant virus. HCV-specific CTLs that respond effectively to low concentrations of peptide have greater potency than those requiring high peptide concentrations. (ii) CTL responses rapidly selecting for HCV escape variants require a low concentration of peptide for stimulation (high avidity), (iii) but if coupled with poor cross-recognition, they are associated with decreased antiviral efficacy and potentially impaired recognition of variant peptides as they emerge (note that there is the least amount of supportive data in this poor cross-recognition paradigm). (iv) CTLs with low functional avidity rarely select for escape variants. The most effective CTL specificities express both functional attributes (in light purple) during the earliest stages of infection and predate the resolution of viremia. Taken together, the data suggest that strong immunity will eradicate HCV infection, weak immunity will drive few mutations, and intermediate immunity will select for escape but allow for persistence, resulting in a broader viral quasispecies.