Conjugation of ubiquitin onto proteins generates a degradation signal or exerts degradation-independent regulatory functions. Ubiquitylation is governed by the antagonistic action of ubiquitin ligases and deubiquitylating enzymes (DUBs). Several recent publications illustrate a balanced interplay of ligases and DUBs at signaling hubs central for longevity and protein homeostasis (proteostasis). In addition, stress-induced alterations of ubiquitin conjugation are emerging as key events that drive aging and contribute to the pathology of age-related diseases. This physiological role of dynamic ubiquitylation events further extends its well-known function in protein regulation and quality control at the cellular level. Recent work thus significantly advances our understanding of the aging process both at a molecular and organismal level.