Oral malodor is caused by volatile sulfur compounds (VSCs) composed mainly of hydrogen sulfide (H(2)S) and methyl mercaptan. In particular, H(2)S is an important compound, since it is a major component of physiologic halitosis. The toxicity of VSCs is similar to that of hydrogen cyanide, and is well investigated. The role of VSCs in reducing collagen in human gingival fibroblasts is one of the main sources of their toxicity to human oral tissues. It has been reported recently that H(2)S may cause apoptosis in several periodontal tissues. In human gingival fibroblasts, H(2)S inhibits not only cytochrome c oxidase activity but also superoxide dismutase activity. The levels of reactive oxygen species are markedly increased, which causes the release of cytochrome c into the cytoplasm, resulting in caspase-9 activation; finally, the executor caspase, caspase-3, is activated. This pathway is commonly observed in cells from all periodontal tissues. Moreover, p53, an apoptotic factor, and phosphorlylated p53, which is the activated form, are increased by H(2)S in keratinocyte stem cells and osteoblasts. H(2)S also increases the expression of Bax, a primary response gene playing an important role in p53-mediated apoptosis, but maintains a lower expression of Bcl-2, an anti-apoptotic factor, in osteoblasts. It is concluded that the Bax apoptotic pathway and the mitochondrial pathway are activated by H(2)S.