This paper deals with the basidiomycete Pleurotus nebrodensis, one of the rare examples of endemic fungi in Italy and Europe. After clarifying the taxonomy of this taxon, including a comparison with a species from China misidentified as “Pleurotus nebrodensis”, we describe the characteristics of its natural habitat, and provide a new morphological description and information on its pilot-scale cultivation, current conservation status according to IUCN criteria and conservation strategies. New ITS region sequences were deposited in GenBank. Furthermore, the antibacterial and anti-cancer properties of P. nebrodensis are mentioned, making it a potential medicinal mushroom. Finally, a critical analysis, on a phylogenetic basis, of the Italian production of substrates inoculated with “P. nebrodensis” strains is also included.