Significance: The thioredoxin (TRX) and glutathione (GSH) pathways are universally conserved thiol-reductase systems that drive an array of cellular functions involving reversible disulfide formation. Here we consider these pathways in Saccharomyces cerevisiae, focusing on their cell compartment-specific functions, as well as the mechanisms that explain extreme differences of redox states between compartments. Recent Advances: Recent work leads to a model in which the yeast TRX and GSH pathways are not redundant, in contrast to Escherichia coli. The cytosol possesses full sets of both pathways, of which the TRX pathway is dominant, while the GSH pathway acts as back up of the former. The mitochondrial matrix also possesses entire sets of both pathways, in which the GSH pathway has major role in redox control. In both compartments, GSH has also nonredox functions in iron metabolism, essential for viability. The endoplasmic reticulum (ER) and mitochondrial intermembrane space (IMS) are sites of intense thiol oxidation, but except GSH lack thiol-reductase pathways. Critical Issues: What are the thiol-redox links between compartments? Mitochondria are totally independent, and insulated from the other compartments. The cytosol is also totally independent, but also provides reducing power to the ER and IMS, possibly by ways of reduced and oxidized GSH entering and exiting these compartments. Future Directions: Identifying the mechanisms regulating fluxes of GSH and oxidized glutathione between cytosol and ER, IMS, and possibly also peroxisomes, vacuole is needed to establish the proposed model of eukaryotic thiol-redox homeostasis, which should facilitate exploration of this system in mammals and plants. © 2013 Mary Ann Liebert, Inc.