Ubiquitination of endogenous proteins is one of the key regulatory steps of protein degradation followed by regulation of proteasome activity. During the last years evidence has increased that proteasome activity is decreased during the aging process in various model systems and that these changes might be causally related to aging and aging associated diseases. Since in most instances ubiquitination is the primary event in target selection, the system of ubiquitination and deubiquitination might be of similar importance. Furthermore, ubiquitination and proteasomal degradation are not completely congruent, since ubiquitination also confers functions different from giving "the kiss of death" to proteins. Depending on mono- and polyubiquitination and on how ubiquitin chains are linked together, ubiquitination is involved in transcriptional regulation, receptor internalization, DNA repair, and stabilization of protein complexes. This review is therefore the first to 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 to discuss potential causes and consequences for aging.