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Human fungal pathogens like Candida albicans respond to host immune surveillance by rapidly adapting their transcriptional programs. Chromatin assembly factors are involved in the regulation of stress genes by modulating the histone density at these loci. Here, we report a novel role for the chromatin assembly-associated histone acetyltransferase complex NuB4 in regulating oxidative stress resistance, antifungal drug tolerance and virulence in C. albicans. Strikingly, depletion of the NuB4 catalytic subunit, the histone acetyltransferase Hat1, markedly increases resistance to oxidative stress and tolerance to azole antifungals. Hydrogen peroxide resistance in cells lacking Hat1 results from higher induction rates of oxidative stress gene expression, accompanied by reduced histone density as well as subsequent increased RNA polymerase recruitment. Furthermore, hat1Δ/Δ cells, despite showing growth defects in vitro, display reduced susceptibility to reactive oxygen-mediated killing by innate immune cells. Thus, clearance from infected mice is delayed although cells lacking Hat1 are severely compromised in killing the host. Interestingly, increased oxidative stress resistance and azole tolerance are phenocopied by the loss of histone chaperone complexes CAF-1 and HIR, respectively, suggesting a central role for NuB4 in the delivery of histones destined for chromatin assembly via distinct pathways. Remarkably, the oxidative stress phenotype of hat1Δ/Δ cells is a species-specific trait only found in C. albicans and members of the CTG clade. The reduced azole susceptibility appears to be conserved in a wider range of fungi. Thus, our work demonstrates how highly conserved chromatin assembly pathways can acquire new functions in pathogenic fungi during coevolution with the host., Author Summary Candida albicans is the most prevalent fungal pathogen infecting humans, causing life-threatening infections in immunocompromised individuals. Host immune surveillance imposes stress conditions upon C. albicans, to which it has to adapt quickly to escape host killing. This can involve regulation of specific genes requiring disassembly and reassembly of histone proteins, around which DNA is wrapped to form the basic repeat unit of eukaryotic chromatin—the nucleosome. Here, we discover a novel function for the chromatin assembly-associated histone acetyltransferase complex NuB4 in oxidative stress response, antifungal drug tolerance as well as in fungal virulence. The NuB4 complex modulates the induction kinetics of hydrogen peroxide-induced genes. Furthermore, NuB4 negatively regulates susceptibility to killing by immune cells and thereby slowing the clearing from infected mice in vivo. Remarkably, the oxidative stress resistance seems restricted to C. albicans and closely related species, which might have acquired this function during coevolution with the host.