As an important post-transcription modification, histone deacetylation plays significant roles in chromatin remodeling and gene expression. The aberrant modification of histone deacetylation leads to various diseases. As a critical member of histone deacetylase (HDAC), HDAC6 serves as a key modulator in many physiological processes. Abnormal expression of HDAC6 gives rise to cancer, neurodegeneration and other diseases. Here, we have reviewed recent advances in physiological, protein structure and development of HDAC6 selective inhibitors.