Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is probably the most important ubiquitously expressed little protein that you have never heard of. Discovered more than 20 years ago, it is now known as a master regulator of redox homeostasis, controlling a plethora of cytoprotective phase II anti-oxidant enzymes. Regulation of gene expression by histone acetyltransferases and histone deacetylases drives the etiology of many age-related human diseases, including osteoarthritis. In Arthritis Research & Therapy, Cai et al. explore systemic histone deacetylase inhibition as a strategy to prevent osteoarthritis and identify a role for Nrf2 in preventing cartilage degeneration.