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1,3-Butadiene (BD) is a gas used heavily in the rubber and plastics industry. BD and its epoxide metabolites have been shown to be carcinogenic and mutagenic in rodents, and BD has been classified by IARC as a group 2A carcinogen. We have examined the role of stereochemistry in species-dependent metabolism and toxicity of BD. Diastereo- and enantioselective synthetic routes to butadiene monoxide (BMO), butadiene bisoxide (BBO), and 3,4-epoxybutane-1,2-diol isomers have been developed. These routes have allowed the development of chiral gas chromatographic and GC/MS analytical procedures for quantitation of these metabolites in biological experiments. We have utilized hepatic microsomes from male B6C3F1 mice and hepatic microsomes and intact hepatocytes from male Sprague-Dawley rats as experimental systems. At 30 min, BMO production from BD was two times higher in mouse hepatic microsomes than in rats, and stereoselective analysis was used to determine the relative formation of (R)- and (S)-BMO. Formation of BBO from both (R)- and (S)-BMO was characterized in rat and mouse microsomal systems. As expected, more BBO was formed in mouse hepatic microsomes (3-4-fold) than in rat hepatic microsomes. No difference in total BBO formed from either isomer was observed in rat microsomes, but in mouse microsomes significantly more BBO was produced from (S)-BMO than from (R)-BMO. The cytotoxicity of each BMO and BBO enantiomer was examined in freshly isolated rat hepatocytes. (R)-BMO showed greater cytotoxicity than (S)-BMO. Stereospecific cytotoxicity was also observed using BBO enantiomers and (meso)-BBO was more cytotoxic than either the (R:R) or the (S:S)-BBO. The results show that stereochemistry plays an important role in BD metabolism and cytotoxicity and for the purposes of risk assessment needs to be compared across species.