Employing organic redox mediators (ORMs) for lithium-oxygen (Li-O-2) batteries has emerged as an important strategy to suppress charging overpotentials. Judicious molecular designs of ORMs can also tailor their redox potential and electron-transfer rate to optimize the catalytic efficiency. However, the stability of ORMs in Li-O-2 cells was scarcely studied. Here, the catalytic efficiency and stability of several important ORMs are assessed through in situ gas analysis and reactivity tests with singlet oxygen. Some well-known ORMs are detrimentally decomposed during the first cycle in Li-O-2 cells, whereas nitroxyl-radical-based ORMs bear the most stable and efficient response. Analogous nitroxyl-radical derivatives further increase round-trip energy efficiency and electron-transfer kinetics. This study underlines chemical stability aspects of ORMs, which are mandatory for the long-term cyclability in Li-O-2 cells. We emphasize that besides the importance of ORMs in these systems and their proper selection, an effective operation of Li-O-2 cells depends also strongly on the stability of the carbonaceous cathodes and the electrolyte solutions. The stability of all the components in these systems is inter-related.