In mice and humans, the size of the peripheral lymphocyte pool remains relatively constant throughout adult life, in the absence of disease. Among the factors that influence the survival and homeostasis of T cells, external stimuli such as infections have long been considered to be of primary importance. However, emerging data indicate that internal stimuli, including self-peptide (presented in association with major-histocompatibility-complex molecules) and cytokines, might also control the size and composition of T-cell pools. Recent evidence suggests that cytotoxic-T-lymphocyte-associated antigen 4, an immune attenuator, contributes significantly to the homeostatic control of T-helper-cell proliferation through mechanisms that are both intrinsic and extrinsic to the T cell.