Maintenance of metal homeostasis is critical to cell survival due to the multitude of cellular processes that depend on one or more metal cofactors. Here, we show that the opportunistic fungal pathogen Candida albicans extensively remodels its metal homeostasis networks to respond to treatment with the antifungal drug fluconazole. Disruption of the ergosterol biosynthetic pathway by fluconazole requires C. albicans adaptation, including increased Cu import and storage, increased retention of Fe, Mn, and Zn, altered utilization of Cu- and Mn-dependent enzymes, mobilization of Fe stores, and increased production of the heme prosthetic group utilized by the enzyme target of fluconazole. The findings offer a new perspective for thinking about fungal response to drug stress that pushes cells out of their metal homeostatic zones, leading them to enact metal-associated adaptation mechanisms to restore homeostasis to survive.