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Until recently, reversible acetylation was thought to occur exclusively in the nucleus. Now it is known that several cytoplasmic processes require reversible acetylation. The first identified cytoplasmic deacetylase was HDAC6, a member of the histone deacetylase (HDAC) family. HDAC6 modulates a-tubulin acetylation and thus can regulate cytoskeletal dynamics and cell motility. HDAC6 has also been shown recently to play an essential role in the cell’s response to misfolded proteins. Using the characterization of HDAC6 as a starting point, in this chapter we review the role of HDACs in the cellular response to misfolded proteins. Specifically, we address how HDACs regulate the formation of aggresomes. We also discuss the relevance of these findings to neurodegenerative disease.