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Deep-sea hypersaline anoxic basins (DHABs) are one of the most hostile environments on Earth. Even though DHABs have hypersaline conditions, anoxia and high hydrostatic pressure, they host incredible microbial biodiversity. Among eukaryotes inhabiting these systems, recent studies demonstrated that fungi are a quantitatively relevant component. Here, fungi can benefit from the accumulation of large amounts of organic material. Marine fungi are also known to produce bioactive molecules. In particular, halophilic and halotolerant fungi are a reservoir of enzymes and secondary metabolites with valuable applications in industrial, pharmaceutical, and environmental biotechnology. Here we report that among the fungal taxa identified from the Mediterranean and Red Sea DHABs, halotolerant halophilic species belonging to the genera <i>Aspergillus</i> and <i>Penicillium</i> can be used or screened for enzymes and bioactive molecules. Fungi living in DHABs can extend our knowledge about the limits of life, and the discovery of new species and molecules from these environments can have high biotechnological potential.