The response of Saccharomyces cerevisiae cells to an aqueous extract of cigarette smoke was studied. Exposure to cigarette smoke extract inhibits yeast growth and results in global changes in gene expression spanning many functional classes of genes. Genes involved in response to oxidative stress are upregulated after a brief exposure to cigarette smoke extract. The effects of cigarette smoke extract on yeast growth can be reversed by treatment with anti-oxidants. Mutants lacking superoxide dismutase gene were hypersensitive to cigarette smoke exposure. YAP1 is a central transcriptional regulator of oxidative stress in yeast. YAP1 dependent expression of beta-galactosidase was enhanced following exposure to cigarette smoke. The overall agreement between our observations and the recently reported effects of cigarette smoke on gene expression in rodent and human cells suggests that yeast can be used as a model system in toxicogenomics studies for monitoring toxic agents and studying the cellular and molecular consequences of exposure to potentially toxic agents.