Naturally occurring salivary antifungal proteins have been of major interest, due to their potential to provide the basis for peptide antimycotics effective in combating fungal infections in the oral cavity or elsewhere. We tested the fungistatic activity of a number of cationic antifungal proteins, with major emphasis on histatin 5, a basic protein secreted by the human parotid and submandibular glands. Histatin 5 inhibited the growth of Candida albicans and that of other medically important Candida species, such as C. kefyr, C. krusei, and C. parapsilosis, with IC 50 values in the range of 10-20 µg/ml. Two Cryptococcus neoformans strains were also sensitive (IC 50 5.2 and 5.6 µg/ml). On the other hand, three C. glabrata strains (ATCC 90030, 2001 and 64677) were entirely insensitive to histatin 5 (IC 50 >225 µg/ml). Four genetically very similar species to C. glabrata, Candida castelli (CBS 4332), Saccharomyces cerevisiae (S288C, BY4741 and CBS 1171), Kluyveromyces delphensis (CBS 2170) and Kluyveromyces bacillisporus (CBS 7720) were all sensitive to histatin 5 (IC 50 2.6-64.6 µg/ml). C. glabrata was also insensitive to other members of the histatin family; histatin 1, 3 and P-113 (IC 50 values in all cases >225 µg/ml). In addition, two entirely different cationic antifungal proteins originating from frog skin, PGLa and magainin 2, also showed a strong reduced activity toward this fungus. Besides the well-described inherent resistance of C. glabrata to azole-derived antifungal agents, our studies indicate that this species is also able to withstand the otherwise detrimental activities of cationic antifungal proteins.