An increased amount of data suggests that chromatin structure and epigenetic regulation are related to polyQ disease pathology. These diseases often exhibit abnormal transcriptional regulation. Epigenetic-related factors and chromatin structure are considered involved in genomic instability of CAG repeats. It has been concluded that disrupted chromatin regulation may be directly involved with the pathophysiology of polyQ diseases. The acetylation of histone by histone acetyl transferase plays an important role in the regulation of gene transcription. Data suggests that expanded polyglutamine proteins alter the histone acetylation and decrease gene expressions. Furthermore, growing data suggest a potential therapeutic role for drugs that target chromatin, such as histone deacetylase (HDAC) inhibitors, in various polyQ models.