Primary CD8+ T cell responses play a major role in controlling infection by many viruses, and CD8+ memory T cells can confer immunity to virus challenge. In this study we report that for many epitope-specific CD8+ T cell populations, the regulation of an important effector molecule, IFN-gamma, changes dramatically over the course of infection. During the acute phase of infection, many CD8+ T cells exhibit a significant lag before producing IFN-gamma in response to Ag contact; in contrast, the onset of IFN-gamma production by memory cells of the same epitope specificity is markedly accelerated. The biological consequences of this improved responsiveness are manifold. Moreover, during the acute phase of the CD8+ T cell response when immunodominance is being established, there is a strong correlation (p = 0.0002) between the abundance of each epitope-specific T cell population and the rapidity with which it initiates IFN-gamma synthesis. Previous studies have indicated that IFN-gamma plays a critical role in determining the immunodominance hierarchy of an on-going T cell response, and in this report we present evidence for an underlying mechanism: we propose that the CD8+ T cells that most rapidly initiate IFN-gamma production may be at a selective advantage, permitting them to dominate the developing T cell response.