Immune escape mutations selected by human leukocyte antigen class I-restricted CD8(+) cytotoxic T lymphocytes (CTLs) can result in biologically and clinically relevant costs to HIV-1 replicative fitness. This phenomenon may be exploited to design an HIV-1 vaccine capable of stimulating effective CTL responses against highly conserved, mutationally constrained viral regions, where immune escape could occur only at substantial functional costs. Such a vaccine might 'channel' HIV-1 evolution towards a less-fit state, thus lowering viral load set points, attenuating the infection course and potentially reducing the risk of transmission. A major barrier to this approach, however, is the accumulation of immune escape variants at the population level, possibly leading to the loss of immunogenic CTL epitopes and diminished vaccine-induced cellular immune responses as the epidemic progresses. Here, we review the evidence supporting CTL-driven replicative defects in HIV-1 and consider the implications of this work for CTL-based vaccines designed to attenuate the infection course.