The protein quality control system, composed of molecular chaperones and proteases, is of vital importance for the maintenance and function of the proteome and the health of the cell. To achieve this, the cellular proteostasis network integrates the protein folding machinery across all compartments of the eukaryotic cell to enable efficient communication and coordinate a rapid response of folding capacity. Quality control in the mitochondria, however, differs from its cytosolic counterpart due to its prokaryotic origin, and is entirely encoded by the nuclear genome. The control and regulatory cross-talk of mitochondrial function in cellular proteostasis is essential for cellular metabolism, organismal development, and lifespan. Consequently, mitochondrial dysfunction has dramatic effects on the development and progression of a number of neurodegenerative diseases, such as Friedreich's ataxia and Parkinson's disease. Studies using Caenorhabditis elegans as a model system have greatly contributed to our current knowledge of inter-compartmental proteostasis on the cellular and organismal levels. Developmental Dynamics 239:1529–1538, 2010. © 2010 Wiley-Liss, Inc.