Chemocompatible disulfide-based probes have long been explored as reporters for dithiol-type enzymes. Disulfide triggercargo constructs are a conceptually simple, modular turn-on design for probes (Fig. ). Ideally, the trigger is attached to the cargo to mask a key structural element, such that (i) the intact probe is fully deactivated (e.g. optically silent), but (ii) trigger reduction causes a cascade that irreversibly restores activity by unmasking (e.g. fluorogenesis), often by simply liberating the cargo (Fig. ). Analysing disulfide trigger-cargo probes' performance shows that both disulfide topology (linear or cyclic), as well as geometry (strained or stabilised), are key to cellular performance since they determine a probe's sensitivity to monothiols. Monothiols are highly concentrated in cells, with 1-8 mM GSH, and an even larger pool of protein thiols (PRSH). To report selectively on redox-active dithiol/disulfide proteins, probes must resist attack by this monothiol background. However, any thiol/disulfide exchange reaction upon linear-topology disulfides irreversibly commits a probe to cargo release (Fig. , Fig. ). This makes linear topology probes nonspecifically labile to cellular monothiols, preventing them from being enzyme-selective reporters in the cellular context. Although some reports have used linear disulfide probes (Fig. ), we believed that selective reporters would require a different design. Cyclic-topology disulfide probes can resist triggering by monothiols in two ways. They can reform the disulfide after the initial thiol-disulfide exchange by expelling the attacking monothiol, or after reduction to the dithiol they can be re-oxidised by other disulfides in their environment: both of which prevent them from committing to cargo release (Fig. ; full discussion in ref. ). The geometry of the cyclic disulfide is critical for these reactions, and so determines the cellular performance of such probes. Strained cyclic disulfides were characterised by Whitesides in the 1990s. Noteworthily, they are kinetically labile, being rapidly and nonspecifically opened by monothiols, and opening is irreversible since disulfide strain disfavours reclosure. Thus in the cellular context, cyclic 7-membered, ETP-type-6-membered, and cyclic 5-membered disulfides cannot be selective substrates for dithiol proteins. Although probes based on cyclic 5-membered disulfides have been published and commercialised as TrxR-selective (Fig. ), their unselectivity and kinetic problems have been demonstrated (Fig. ). Alicyclic 6-membered disulfides (1,2-dithianes), however, are unstrained and are stable against monothiols. Monocyclic and annelated bicyclic 1,2-dithianes were recently used as reductive triggers that resist GSH and TrxR , yet can be harnessed in probes that are selective for Trx (Fig. ) (see Supporting Note 1). Here, we wished to leverage these design principles to develop modular probes that resist the cellular monothiol background but would report selectively on TrxR1 activity in live cells. Analysing thermodynamics, kinetics, and reaction pathways led us to design novel cyclic 6-membered selenenylsulfides as reduction triggers. We developed scalable syntheses for a palette of cumulative-release fluorogenic probes with a modular design. A range of cell-free and cellular assays including genetic knockout, knock-in, chemical inhibition, selenium supplementation and depletion studies, confirmed their outstanding selectivity for reporting on cellular TrxR1. The solubilised probe RX1, for TrxR1-redox-probe 1, is a particularly rapid and stable cellular fluorescence imaging reporter of TrxR1 activity. We could apply RX1 to enable the first high-throughput selective cellular screening for TrxR inhibitors, which indicated SNAr-based inhibitors may be favoured chemotypes for future development. RX1 offers a flexible platform for TrxR1 imaging as well as further development of TrxR probes and prodrugs; and the analysis guiding its development can light a path for other key redox-active enzymes.