Thy-1 (CD90) is a small GPI-anchored protein that is particularly abundant on the surface of mouse thymocytes and peripheral T cells. T cell proliferation and cytokine synthesis in response to Thy-1 cross-linking by specific mAb suggests a role for Thy-1 in mouse T lymphocyte activation. However, a physiological ligand or counterreceptor for murine Thy-1 in the lymphoid compartment has not yet been identified. Thy-1 cross-linking, in the context of strong costimulatory signaling through CD28, results in an activating signal that can at least partially substitute for TCR signaling during mouse T cell activation. Remarkably, Thy-1 cross-linking also results in the potent costimulation of T cells activated through the TCR. This novel dual signaling capacity suggests a possible role for Thy-1 in the maintenance of T cell homeostasis in the absence of TCR triggering, as well as potentiating Ag-induced T cell responses.