V-ATPases are structurally conserved and functionally versatile proton pumps found in all eukaryotes. The yeast V-ATPase has emerged as a major model system, in part because yeast mutants lacking V-ATPase subunits (vma mutants) are viable and exhibit a distinctive Vma- phenotype. Yeast vma mutants are present in ordered collections of all non-essential yeast deletion mutants, and a number of additional phenotypes of these mutants have emerged in recent years from genomic screens. This review summarizes the many phenotypes that have been associated with vma mutants through genomic screening. The results suggest that V-ATPase activity is important for an unexpectedly wide range of cellular processes. For example, vma mutants are hypersensitive to multiple forms of oxidative stress, suggesting an antioxidant role for the V-ATPase. Consistent with such a role, vma mutants display oxidative protein damage and elevated levels of reactive oxygen species, even in the absence of an exogenous oxidant. This endogenous oxidative stress does not originate at the electron transport chain, and may be extra-mitochondrial, perhaps linked to defective metal ion homeostasis in the absence of a functional V-ATPase. Taken together, genomic data indicate that the physiological reach of the V-ATPase is much longer than anticipated. Further biochemical and genetic dissection is necessary to distinguish those physiological effects arising directly from the enzyme's core functions in proton pumping and organelle acidification from those that reflect broader requirements for cellular pH homeostasis or alternative functions of V-ATPase subunits.