Glutathione (GSH), a ubiquitous tripeptide molecule, regulates numerous cellular processes. In biological systems, GSH exists either in its reduced or oxidized (GSSG) forms, and the ratio GSH/GSSG serves as an informative marker of oxidative stress. However, little is known regarding the effects of natural genetic variation on GSH homeostasis. In this project, we used inbred mouse strains to determine the effects of genetic background on tissue GSH levels and GSH/GSSG. We measured GSH and GSSG levels in livers and kidneys isolated from young- adult mice representing 30 genetically diverse mouse strains, and employed in silico mapping to identify protein-coding genes associated with GSH homeostasis. We also quantified tissue levels of GSH related phenotypes in old mice representing 19 strains Heritability of GSH levels and GSH/GSSG was estimated. Our results indicate that GSH levels and GSH/GSSG are regulated by genetic background throughout the mammalian life span.