A new class of hydrogen sulfide (H(2)S)-donating hybrids combined with pharmacologically active compounds is presented in this article. The pharmacological profiles of some hybrid lead compounds in the areas of inflammation, H(2)S-donating diclofenac (ACS 15); cardiovascular, H(2)S-donating aspirin (ACS 14); urology, H(2)S-donating sildenafil (ACS 6); and neurodegenerative, H(2)S-donating latanoprost (ACS 67) for glaucoma treatment and H(2)S-donating levodopa (ACS 84) for Parkinson's disease, are described. The new H(2)S-releasing hybrids demonstrate remarkable improvement in activity and tolerability as compared with the related parent compounds, suggesting an active pharmacological role for H(2)S. Finally the mechanism(s) of action of glutathione-dependent and independent, and of gas (H(2)S) release (spontaneous or enzymatic) and its implications for clinical pharmacology perspectives will be also discussed.