Mitochondria are essential for a variety of cellular functions, including ATP production, lipid biosynthesis, and calcium homeostasis. Moreover, a number of major cell signaling pathways, including apoptosis, require mitochondria. Consistent with a major role of mitochondria in the control of cell function, defects of these organelles are thought to induce a variety of pathologies ranging from diabetic neuropathies to Parkinson's and Alzheimer's diseases. Here we discuss the role of ubiquitin (Ub) conjugation in the maintenance of mitochondrial function. We found that at least four putative RING finger E3 Ub ligases, the main determinants of substrate specificity in the ubiquitination system, localize to mitochondria. Our data also demonstrate that mitochondrial membrane dynamics is under the regulatory control of the Ub-conjugation system. These and data recently published by others indicate that the Ub-conjugation system and proteasomal degradation of mitochondrial proteins might be vital for the maintenance of mitochondrial homeostasis and lead to cell demise when dysfunctional.