The invasive fungal infections have been evolving for the last few decades and become a crucial factor that negatively affects the survival ability of the patients. Moreover, developing new resistance mechanisms of infectious organisms to the antifungal drugs make this problem more critical. In this study, we identified four different genes PDR16 and PMP3, RMD9 and SWH1which are resistant to amphotericin B and caspofungin, respectively, in Saccharomyces cerevisiae. We also screened whole yeast genome at transcriptional level via microarray analysis and identified metabolic pathways affected by these antifungal drugs. In addition, we applied several characterization methods including physiological and morphological analyses to understand the resistance mechanisms. We found that rmd9 mutants were extremely hyperpolarized and pdr16 and pmp3 mutants were depolarized when compared to control group. In contrast, overexpression of SWH1 increased the membrane potential of wild type cells. Further analyses showed that the absence of RMD9 disrupts the cellular morphology. To show that these genes are clinically important, Candida albicans orthologs of PDR16 and PMP3 were cloned and their roles in amphotericin B drug resistance were confirmed. RMD9 and SWH1 have no known C. albicans orthologs, so the confirmation with pathogenic yeast genome could not be performed against caspofungin. This study was financially supported by The Scientific and Technological Research Council of Turkey (TUBITAK 212T186) and Academy of Sciences of Czech Republic (AS CR).