Significance: Hydrogen sulfide (H ₂ S) plays critical roles in redox biology, and its regulatory effects are tightly controlled by its cellular location and concentration. The imbalance of H ₂ S is believed to contribute to some pathological processes. Recent Advances: Downregulation of H ₂ S requires chemical tools such as inhibitors of H ₂ S-producing enzymes and H ₂ S scavengers. Recent efforts have discovered some promising inhibitors and scavengers. These advances pave the road toward better understanding of the functions of H ₂ S. Critical Issues: Precise H ₂ S downregulation is challenging. The potency and specificity of current inhibitors are still far from ideal. H ₂ S-producing enzymes are involved in complex sulfur metabolic pathways and ubiquitously present in biological matrices. The inhibition of these enzymes can cause unwanted side effects. H ₂ S scavengers allow targeted H ₂ S clearance, but their options are still limited. In addition, the scavenging process often results in biologically active by-products. Future Directions: Further development of potent and specific inhibitors for H ₂ S-producing enzymes is needed. Scavengers that can rapidly and selectively remove H ₂ S while generating biocompatible by-products are needed. Potential therapeutic applications of scavengers and inhibitors are worth exploring. Antioxid. Redox Signal . 36, 294–308.