TrxR's position as a central redox node in diverse physiological processes drives the hitherto-unmet need for precise, selective molecular probes to characterise and decrypt its activity in cell biology and in physiological responses to stress. Furthermore, the significant and potentially unique dysregulation of cellular redox systems in pathology, notably of the thioredoxin system, opens exciting vistas cellular hits only (2) shared hits (7) cellular pIC 50 cell-free pIC 50 cell-ree hits only (9) inacti e (993) towards using TrxR-selective probes as tools both to study and ultimately to diagnose pathologies featuring redox dysregulation, such as autoimmune diseases and cancer. Finally, if such molecular probes are also modular designs, they offer to meet the full spectrum of needs in translational chemical biology: from redox-triggered diagnostics of diverse modalities (that are predictive of arbitrary cargo release), to the redox-triggered prodrugs that may allow targeting bioactivity selectively to the identified pathological tissues. The selenenylsulfide-based probe RX1 exploits a "Selenium Required" mechanism-based design to perform as the first TrxR1-selective, modular, cargo-releasing cellular probe system. The cyclic topology of the stabilised selenenylsulfide substrates, and the mechanistic bias of the 5-exo-trig selenolate cyclisation, are both required for this performance. Its design is robust, yet its high selectivity for mammalian TrxR1 is accompanied by fast kinetics of processing and cargo release. Its true off-to-on optical performance (zero pre-activation background, to bright and photostable environment-independent fluorescence) and its cell-retained localisation permit cellresolved imaging with excellent signal-to-noise ratios. RX1 will thus be directly useful for redox biology studies quantifying TrxR1 activity in physiology and disease. Moreover, its high-quality performance in high-throughput screening can earn it a crucial place in development pipelines for selective cellular inhibitors of TrxR1: a goal of significant pharmaceutical interest, and one which we believe will more broadly enlighten the field towards the scope for high-selectivity inhibitors, whether tempered electrophiles or noncovalents.