Significance: Cancer is a complex and heterotypic structure with a spatial organization that contributes to challenges in therapeutics. Enzymes associated with producing the gasotransmitter hydrogen sulfide (H₂S) are differentially expressed in tumors. Indeed, critical and paradoxical roles have been attributed to H₂S in cancer-promoting characteristics by targeting both cancer cells and their milieu. This review focuses on the evidence and knowledge gaps of H₂S on the tumor redox microenvironment and the pharmacological effects of H₂S donors on cancer biology.

Recent Advances: Endogenous and pharmacological concentrations of H₂S evoke different effects on the same cell type: physiological H₂S concentrations have been associated with tumor development and progression. In contrast, pharmacological concentrations have been associated with anticancer effects.

Critical Issues: The exact threshold between the promotion and inhibition of tumorigenesis by H₂S is largely unknown. The main issues covered in this review include H₂S-modulated signaling pathways that are critical for cancer cells, the potential effects of H₂S on cellular components of the tumor microenvironment, temporal modulation of H₂S in promoting or inhibiting tumor progression (similar to observed for inflammation), and pharmacological agents that modulate H₂S and which could play a role in antineoplastic therapy.

Future Directions: Given the complexity and heterogeneity of tumor composition, mechanistic studies on context-dependent pharmacological effects of H₂S donors for cancer therapy are necessary. These studies must determine the critical signaling pathways and the cellular components involved to allow advances in the rational use of H₂S donors as antineoplastic agents. Antioxid. Redox Signal. 40, 250–271.