Histone deacetylases (HDACs), or lysine deacetylases (KDAC), are epigenetic regulators that catalyze the removal of acetyl moieties from the tails of lysine residues of histones and other proteins. To date, eighteen HDAC family members (HDAC1-11 and SIRT1-7) have been identified and grouped into four classes according to their homology to yeast histone deacetylases. HDACs play an important role in regulating gene transcription as well as a variety of cellular functions. Recent studies have found that HDAC6 (α-tubulin deacetylase) has the novel ability to capture α-tubulin as a substrate and regulate the physiological level of its acetylated form. In addition, a growing body of evidence suggests that α-tubulin deacetylase plays a critical role in the cellular response to the accumulation of misfolded and aggregated proteins, which are a prominent pathological feature common to many age-related neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. Therefore, the role of α-tubulin deacetylase and its potential as a therapeutic target for neurodegenerative diseases are areas of rapidly expanding investigation. Here we review the research of the role played by HDAC6 in the regulation of tubulin modification and aggresome formation. We also summarize the specific inhibitors of HDAC6 and address reports that implicate HDAC6 in various neurodegenerative disorders.