Candidiasis, aspergillosis, and mucormycosis cause the majority of nosocomial fungal infections in immunocompromised patients. Using an unbiased transcriptional profiling in PBMCs exposed to the fungal species causing these infections, we found a core host response in healthy individuals that may govern effective fungal clearance: it consists of 156 transcripts, involving canonical and non-canonical immune pathways. Systematic investigation of key steps in antifungal host defense revealed fungal-specific signatures. As previously demonstrated, Candida albicans induced type I and Type II interferon-related pathways. In contrast, central pattern recognition receptor, reactive oxygen species production, and host glycolytic pathways were down-regulated in response to Rhizopus oryzae, which was associated with an ER-stress response. TLR5 was identified to be uniquely regulated by Aspergillus fumigatus and to control cytokine release in response to this fungus. In conclusion, our data reveals the transcriptional profiles induced by C. albicans, A. fumigatus, and R. oryzae, and describes both the common and specific antifungal host responses that could be exploited for novel therapeutic strategies.