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Hydrogen Sulfide (H₂S), an endogenously produced gasotransmitter, is involved in various important physiological and disease conditions, including vasodilation, stimulation of cellular bioenergetics, anti-inflammation, and pro-angiogenesis. In cancer, aberrant up-regulation of H₂S-producing enzymes is frequently observed in different cancer types. The recognition that tumor-derived H₂S plays various roles during cancer development reveals opportunities to target H₂S-mediated signaling pathways in cancer therapy. In this review, we will focus on the mechanism of H₂S-mediated protein persulfidation and the detailed information about the dysregulation of H₂S-producing enzymes and metabolism in different cancer types. We will also provide an update on mechanisms of H₂S-mediated cancer progression and summarize current options to modulate H₂S production for cancer therapy.