The aim of this study is to select a cisplatin resistant Saccharomyces cerevisiae strain as a model organism to look for new molecular markers of cisplatin resistance and the identification of mechanisms/interactions involved. A cisplatin resistant S. cerevisiae strain was obtained after continuous exposure to the drug during 80 days. Then, total protein extraction, purification and identification were carried out, in wild type (wt) and resistant strains, by tandem mass spectrometry using a "nano HPLC-ESI-MS/MS" ion trap system. The increase in emPAI (resistant vs wt strains) was calculated to study the increase in protein expression. "Genemania" software (http://www.Genemania.org/) was used to compare the effects, functions and interactions of proteins. The selected cisplatin resistant strain showed 2.5 times more resistance than the wt strain (for the ID50 value) and 2.78 times more resistant for the ID90 value. The long-term exposure to cisplatin induced resistance in S. cerevisiae, obtaining an increased expression of QCR2, QCR1, ALDH4, ATPB, ATPA, SCW10, HSP26, ATPG, and PCKA proteins. The overexpression of the above-mentioned proteins suggests that they could be involved in cisplatin resistance. The resistance acquisition process is complex and involves the activation of multiple mechanisms that interact together.