The gaseous signalling molecule hydrogen sulphide (H2S) regulates a range of cellular processes by causing the sulphydration of Cys residues (that is, the formation of Cys–SSH groups) in target proteins. Protein Tyr phosphatases (PTPs) use an essential Cys (Cys215) in their catalytic site to dephosphorylat e Tyr residues in target proteins. Krishnan et al. now report that the production of H2S upon endo­ plasmic reticulum (ER) stress results in the sulphydration and consequent inhibition of PTP1B, and that this promotes signalling by one branch of the unfolded protein response (UPR) pathway. The authors first measured PTP1B phosphatase activity in vitro, in the presence or absence of H2S, observing that PTP1B can be inhibited by this molecule. PTP1B inactivation by H2S is reversible, as its catalytic activity was restored by the addition of reducing agents that are known to reverse sulphydration. Using mass spectrometry, the authors established that Cys215 is specifically sulphydrated in response to H2S, and further experiments confirmed that PTP1B is sulphydrated at Cys215 in vivo. Together, these data reveal that PTP1B is sulphydrated and that its catalytic activity is inhibited by this modification. But, in what physiological set­ ting might sulphydration regulate PTP1B activity? PTP1B is localized to the ER and has been implicated in UPR signalling, which is activated in response to ER stress. As the production of H2S by the enzyme cystathionine γ­lyase (CSE) has also P O S TT R A N S L AT I O N A L M O D I F I C AT I O N