Specific medical interventions and changes in the host of ever-expanding immunocompromised population due to the rise of AIDS, transplantation, and cancer therapies have led to the emergence of uncommon but medically important fungal pathogens. Although Candida albicans and Aspergillus fumigatus remain the most frequent pathogens of invasive fungal infections, uncommon Candida and Aspergillus species can also cause serious infections. Other uncommon emerging fungal pathogens belong to the group of Zygomycetes, to hyaline moulds including Fusarium, Scedoporium, Acremonium, and Paecilomyces, to dematiaceous fungi including Alternaria, Curvularia, Bipolaris, and Exophiala, and to other yeasts like Saccharomyces cerevisiae and Rhodotorula mucilaginosa and Trichosporon species. Infections caused by these pathogens are often associated with poor outcome and require highly aggressive strategies of antifungal therapy. Decreased susceptibility to fluconazole and/or amphotericin B is observed among isolates of uncommon Candida species such as C. kefyr, C. lusitaneae, C. guilliermondii, C. famata, C. rugosa, C. inconspicua, and C. lambica. Newer azoles and echinocandins may exhibit stronger activity against these isolates. The newly described species C. orthopsilosis and C. metapsilosis, which are genetically related with C. parapsilosis, are susceptible to amphotericin B, echinocandins and azoles; although fluconazole MICs are higher and anidulafungin MICs are lower than those of C. parapsilosis. Some isolates of C. glabrata cryptic species C. nivariensis and C. bracarensis may exhibit significant in vitro resistance to itraconazole, voriconazole, fluconazole and flucytosine. Newly described Aspergillus species belonging to A. fumigatus complex (A. udagawae, N. pseudofischeri, A. lentulus), A. ustus complex (A. calidoustus), A. versicolor complex (A. sydowii), A. niger complex (A. tubingensis) and A. nidulans complex (E. quadrilineata) demonstrate decreased susceptibility to antifungal drugs including amphotericin B and the new triazoles. Zygomycetes are usually resistant to most antifungal drugs with amphotericin B and posaconazole exhibiting the strongest in vitro activity. In vitro testing of Fusarium spp. and Acremonium spp. has shown decreased susceptibility to most antifungal agents. Scedoporium spp. demonstrate resistance to currently available antifungals, with albaconazole and voriconazole being the most active. Dematiaceous fungi are usually susceptible to amphotericin B and the new triazoles with slightly higher MICs for voriconazole. Trichosporon spp. are mostly resistant to flucytosine and echinocandins, susceptible to azoles with voriconazole being the most potent compound and susceptible to amphotericin B with the exception of T. asahii. The new advances in antifungal chemotherapy give more options to treat infections caused by these uncommon fungal pathogens but require a good knowledge of the susceptibility profiles.