Trx1 is recognized as one of the most important regulators of cellular and organismal redox homeostasis (Gromer et al, 2004) . In particular, intracellular Trx1 counteracts oxidative stress, promotes cell growth and inhibits apoptosis. Under conditions of oxidative stress, Trx1 is released by cells and accumulates at sites of inflammation (Nordberg and Arner, 2001) . Numerous studies have reported that secretory Trx1 influences effector functions and proliferation of lymphocytes (Nakamura et al, 1997) . However, proteins and pathways coupling extracellular Trx1 redox activity to defined cellular responses have remained unknown. In this study, we addressed the question regarding which lymphocyte surface receptors are targeted and regulated by the redox activity of extracellular Trx1. For this purpose, we made use of a mechanism-based kinetic trapping approach to capture mixed disulfide intermediates formed between exogenous Trx1 and its target proteins on the cell surface of living cells. Activity-based techniques offer the opportunity to identify interactions too short-lived to be detectable by conventional methods. To our knowledge, this is the first reported application of kinetic trapping to identify novel target proteins of mammalian Trx1 and the first application of this technique to the surface of intact cells. We demonstrate that Trx1 interacts with intraand extracellular target proteins in a highly selective manner, guided by specific protein-protein recognition rather than random encounters with disulfide bonds.