The emergence of less common, but clinically important, fungal pathogens including the rare yeasts has contributed to the substantial morbidity and mortality observed in immunocompromised patients. These organisms can be resistant or refractory to existing antifungal agents. We sought to evaluate the activity of the new triazole isavuconazole against these difficult pathogens.MICs of isavuconazole, voriconazole, posaconazole, fluconazole, amphotericin B and flucytosine were determined for 54 Trichosporon, 7 Geotrichum capitatum, 18 Saccharomyces cerevisiae, 11 Pichia and 14 Rhodotorula species in accordance with the M27-A2 reference method. Minimum fungicidal concentrations were also measured for each agent.Isavuconazole demonstrated excellent in vitro activity against each species tested. MIC(90) values ranged between 0.125 and 0.25 mg/L against Trichosporon isolates, and between 0.03 and 0.5 mg/L against the other yeast tested. The geometric mean MICs of isavuconazole were similar to those of voriconazole and similar or less than those of posaconazole, fluconazole, amphotericin B and flucytosine for all species tested. This activity was also maintained against one Trichosporon asahii and nine Rhodotorula isolates that were resistant to fluconazole.Isavuconazole is a welcome addition to the growing antifungal armamentarium with potent in vitro activity against emerging yeast pathogens. Although this agent may be useful in the treatment of the rare yeasts, clinical data are needed to verify these results.