This review discusses the control exerted by natural CD4(+) CD25(+) regulatory T cells (natural T(reg) cells) during infectious processes. Natural T(reg) cells may limit the magnitude of effector responses, which may result in failure to adequately control infection. However, natural T(reg) cells also help limit collateral tissue damage caused by vigorous antimicrobial immune responses. We describe here various situations in which the balance between natural T(reg) cells and effector immune functions influences the outcome of infection and discuss how manipulating this equilibrium might be exploited therapeutically.