The important life-supporting role of hydrogen sulfide (H₂S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H₂S had only been known for its toxicity and environmental hazard. Physiological importance of H₂S has been appreciated for about a decade. It started by the discovery of endogenous H₂S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H₂S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H₂S. The physiological functions of H₂S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H₂S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes, cirrhosis, inflammation, sepsis, neurodegenerative disease, erectile dysfunction, and asthma, to name a few. Many new technologies have been developed to detect endogenous H₂S production, and novel H₂S-delivery compounds have been invented to aid therapeutic intervention of diseases related to abnormal H₂S metabolism. While acknowledging the challenges ahead, research on H₂S physiology and medicine is entering an exponential exploration era.