Yeast Saccharomyces cerevisiae is an ideal model organism for studying molecular mechanisms of the stress response provoked by metals. In this work, yeast cells response to iron (Fe3+) or lead (Pb2+) exposure was tested and compared. Survival test was used to determine testing doses of metal ions-for Fe3+ it was 4 mM and for Pb2+ 8 mM. These (high, over-loaded) doses provoked comparable values of growth inhibition, but different values in vitality measurement. The percentage of metabolically active cells, determined by fluorescent FUN-1 dye, was lower in Pb2+ than in Fe3+ treated cells. Besides, endogenous antioxidant defence systems in the cells treated with Pb2+ were less efficient compared to Fe3+. At the mitochondrial level, the effects of metal ions were in correlation with the results of cell metabolic activity. The mitochondrial proteome of Pb2+ treated cells showed the domination of protein downregulation. Yeast cells treated either with Fe3+ or Pb2+ shared 19 common significantly changed proteins. The affected proteins were involved in different cellular process and amongst them only five proteins belong to energy and carbohydrate metabolism, and protein biosynthesis. Based on all obtained results, it is possible to conclude that the effects of Fe3+ and Pb2+ on yeast cells show rather specific patterns of toxicity and stress response.