Functional genetic suppression interactions occur when the phenotypic defects caused by one mutation are rescued by a mutation in a second gene. To explore the principles of genetic suppression, we collected both literature-curated and unbiased experimental data to map a large-scale suppression network among yeast genes. We found that most suppression pairs involve functionally related genes that are often co-annotated or co-expressed, or that are encoding co-localized proteins or members of the same pathway or complex. Although the suppression network includes interactions identified in other genetic networks, most suppression interactions identify novel functional relationships. For example, we exploited the suppression network to assign a possible function as a novel phospholipid scramblase for the previously uncharacterized gene ANY1 (YMR0101W), a detailed mechanistic prediction that could not be made using other available genetic interaction data. Genetic suppression also involved general regulatory mechanisms associated with protein degradation, mRNA decay, and metabolic rewiring. Whole-genome sequencing of >300 yeast strains, many of which were derived from the yeast deletion mutant collection, revealed additional frequent loss-of-function mutations in a set of specific genes, including WHI2, IRA1, IRA2, and RIM15, all of which encode negative regulators of Ras signaling and its role in cell cycle progression. These mutations do not affect exponential cell growth but cause a delay in the onset of stationary phase, which appears to select for their enrichment within a propagating population. Our data allow us to formulate some fundamental mechanisms of functional suppression.