The past decade has witnessed the discovery of hydrogen sulfide (H 2 S) as a new signalling molecule. Its ability to act as a neurotransmitter, regulator of blood pressure, immunomodulator or anti-apoptotic agent, together with its great pharmacological potential, is now well established. Notwithstanding the growing body of evidence showing the biological roles of H 2 S, the gap between these roles and the actual mechanism(s) behind these processes is getting larger. We propose a way that protein cysteine residues can be modified to form protein persulfides (P-SSH) and explain how this process is controlled in a physiologically relevant fashion. This article provides an overview of H 2 S signalling in the human body with particular emphasis on the latest discoveries regarding the mechanisms of protein persulfidation and depersulfidation, as well as about the biological reactivity of persulfides and their role in health and disease.