Mono- or polyubiquitination events are post-translational modifications that can target proteins for degradation or modify their function; they can be reversed by deubiquitinases, or DUBs, most of which are cysteine proteases. Three recent reports demonstrate that different DUBs are susceptible to regulation by reversible oxidation. In two of the studies, from Ye and colleagues and Komander and colleagues, the authors initially observed that several human DUBs purified from HEK293 cells or bacteria showed low catalytic activity that could be stimulated by the addition of the reducing agent DTT. Those DUBs could also easily, and reversibly, be inactivated by reactive oxygen species (ROS), hinting at the existence of a regulatory redox switch. Komander and colleagues, by using sulfenylation-reactive click chemistry, identified the catalytic Cys103 of the OTU family member A20 as the residue being oxidized. They then obtained high-resolution crystal structures of A20 in various states of oxidation; these structures indicated that Cys-SOH within the catalytic center is a stabilized intermediate protected from further oxidation, which could readily be reduced by DTT. Ye's group, investigating DUBs from the USP and UCH families, also concluded that the catalytic cysteine is the target of oxidation. They went on to demonstrate that DUB inhibition by oxidative stress in vivo results in a quantitatively correlated increase in PCNA monoubiquitination, which is a well-characterized response to DNA damage. These observations are in agreement with the findings by Huang and colleagues implicating the oxidation of deubiquitinase USP in maintaining levels of monoubiquitinated PCNA during oxidative stress. Together, these studies indicate that the deubiquitination machinery is responsive to the redox state of cells and might therefore play key roles in various ROS-mediated cellular processes. (Nat. Commun. 4, 1568, doi:10.1038/ncomms2532 and Nat. Commun. 4, 1569, doi:10.1038/ncomms2567, published online 5 March 2013; Cell Rep. 2, 1475–1484, 2012)