Ubiquitination ofendogenous proteins is one of the key regulatory steps that guides protein degradation through regulation of proteasome activity. During the last years evidence has accumulated that proteasome activity is decreased during the aging process in various model systems and that these changes might be causally related to aging and age-associated diseases. Since in most instances ubiquitination is the primary event in target selection, the system ofubiquitination and deubiquitination might be of similar importance. Furthermore, ubiquitination and proteasomal degradation are not completely congruent, since ubiquitination confers also functions different from targeting proteins for degradation. Depending on mono- and polyubiquitination and on how ubiquitin chains are linked together, post-translational modifications of cellular proteins by covalent attachment of ubiquitin and ubiquitin-like proteins are involved in transcriptional regulation, receptor internalization, DNA repair, stabilization of protein complexes and autophagy. Here, we summarize the current knowledge regarding the ubiquitinome and the underlying ubiquitin ligases and deubiquitinating enzymes in replicative senescence, tissue aging as well as in segmental progeroid syndromes and discuss potential causes and consequences for aging.