Therapeutic inhibition of histone deacetylase (HDAC) enzymes has been widely reported for the treatment of many cancers. Recently, increasing evidence of HDACs playing a role in regulating inflammation and immunity has triggered more in-depth investigations on how pharmacologic HDAC inhibitors could be beneficial in treating inflammatory and autoimmune diseases. Initial investigations of HDAC enzymes focused on their ability to regulate gene transcription by removing acetyl groups from lysine residues of core histone proteins. Current research indicates a broad repertoire of non-histone proteins that could also act as substrates for HDAC enzymes, further expanding their regulatory potential in cell processes. There are 18 known HDAC enzymes classified based on structure and function into classes I-IV. As pan-selective HDAC inhibitors have been reported to show adverse side effects, isoform-selective inhibitors are becoming more desirable as pharmacologic agents. In this review, we discuss the current understanding of how HDAC6 contributes to the pathogenesis of systemic lupus erythematosus (SLE), therefore making it a suitable candidate for selective pharmacologic inhibition.