This research shows that acidic environments, like those found in inflamed tissues and inside immune cells, make the fungus Cryptococcus neoformans more resistant to the antifungal drug fluconazole. The fungus adapts to acidic conditions by using an alternative iron uptake system that increases the production of protective compounds (ergosterol) in its cell membrane. Understanding this pH-dependent resistance mechanism could help develop better treatment strategies for cryptococcal infections in patients with compromised immune systems.