Recent studies have shown that interleukin-15 (IL-15) is produced during acute HIV and SIV infection, and may impact viremia and viral set point. This is further supported by the findings that administration of IL-15 during acute SIV infection dramatically increases viral set point. Although the role of intrinsic IL-15 during chronic infection is much less defined, in vivo administration of IL-15 does not increase viral replication in SIV-infected animals. Recent data also suggest that IL-15 acts, not only on CD8+ T cells and natural killer cells, but also on effector memory CD4+ T cells. IL-15 clearly expands very different CD4+ T cell subpopulations than IL-2 in SIV-infected animals, and may be useful for the restoration of effector memory CD4+ T cells that are depleted early in HIV and SIV infection. Understanding IL-15's role in SIV infection may help us to design novel therapeutic approaches to HIV infection.