Abstract: Propolis, a natural product of plant resins, is used by the bees to seal holes in their honeycombs and protect the hive entrance. However, propolis has also been used in the folk medicine for centuries. Here, we apply the power of Saccharomyces cerevisiae as a model organism for studies of genetics, cell biology, and genomics aiming to understand how propolis affects fungi at cellular level. Propolis is able to induce an apoptosis cell death response. However, increased exposure to propolis provides a corresponding increase in the necrosis response. We showed that cytochrome c but not endonuclease G Nuc1p, is involved in the propolis-mediated cell death in S. cerevisiae. We also observed that the metacaspase YCA1 gene is important for propolis-mediated cell death. To elucidate the gene functions that may be required for propolis-sensitivity in eukaryotes, the full collection of about 4,800 haploid S. cerevisiae deletion strains was screened for propolis-sensitivity. We were able to identify 138 deletion strains that have different degrees of propolis-sensitivity when compared to the corresponding wild-type strain. Systems biology revealed enrichment for genes involved in mitochondrial electron transport chain, vacuolar acidification, negative regulation of transcription from RNA polymerase II promoter, regulation of macroautophagy associated with protein target to vacuole and cellular response to starvation. Validation studies indicated that propolis sensitivity is dependent on the mitochondrial function, and vacuolar acidification and autophagy are important for yeast cell death caused by propolis.