Here, we sought to develop TrxR-selective molecular probes that noninvasively report TrxR activity in live cells. We focused on chemical designs to monitor enzymatic turnover by irreversible accumulation of signal, in the form of an activated probe. We additionally required the probes to be modular: i.e. the same approach should be applicable to activating arbitrary cargos, including drugs. This is of particular interest since redox dysregulation, including upregulation of TrxR activity and expression, is correlated to disease progression, severity, and resistance to conventional therapeutics, in a range of pathologies. These include nearly all solid tumors (hypoxia-induced gene expression shifts), as well as auto-immune and inflammatory conditions (redox signaling and microenvironment effects). Developing modular strategies to activate imaging agents (for diagnostics) as well as drugs (for redox-targeted therapeutics) could therefore be a powerful approach not just to understand, but also to usefully respond to cellular redox activity in health and in disease.