Methylmercury (MeHg) is an important environmental pollutant that causes severe disorders of the central nervous system, but the mechanism underlying its toxicity and the corresponding biological defense mechanisms remain largely unknown. Saccharomyces cerevisiae (S. cererisiae) yeast cells were used to elucidate the defense mechanisms against MeHg toxicity and to search for novel genes involved in MeHg resistance. S. cerevisiae is a eukaryotic organism that possesses many gene products that are functionally similar to those of mammals such as humans. We have previously reported that Cdc34 and Rad23 confer MeHg resistance to yeast cells. Interestingly, the both proteins are related to ubiquitin-proteasome system (UP system) that is involved in the intracellular degradation of proteins. In our detailed experiments, we found that the UP system might play an important role in lending protection against MeHg toxicity. This review summarizes the results of our studies on the role of the UP system as a defense mechanism against MeHg toxicity in yeast cells. © 2011 The Pharmaceutical Society of Japan.