Intracellular redox imbalance is mainly caused by overproduction of reactive oxygen species (ROS) or weakness of the natural antioxidant defense system. It is involved in the pathophysiology of a wide array of human diseases. Hydrogen sulfide (H 2S) is now recognized as the third “gasotransmitters” and proved to exert a wide range of physiological and cytoprotective functions in the biological systems. Among these functions, the role of H 2S in oxidative stress has been one of the main focuses over years. However, the underlying mechanisms for the antioxidant effect of H 2S are still poorly comprehended. This review presents an overview of the current understanding of H 2S specially focusing on the new understanding and mechanisms of the antioxidant effects of H 2S based on recent reports. Both inhibition of ROS generation and stimulation of antioxidants are discussed. H 2S-induced S-sulfhydration of key proteins (e.g., p66Shc and Keap1) is also one of the focuses of this review.