Normal and pathogenic cells require a menu of metal nutrients for optimal growth, but also strategies to mitigate toxicity associated with misregulated or excessive levels of metals, including copper. Situations in which cells need to adjust copper homeostasis in response to stress present opportunities to manipulate cellular copper as a therapeutic strategy. Our lab has previously shown that the opportunistic fungal pathogen Candida albicans makes significant adjustments related to metallohomeostasis upon treatment with fluconazole, a member of the azole family of antifungal agents that are used clinically for treatment of C. albicans infections.1 Here, I will describe our recent progress in identifying metal chelators and metal trafficking inhibitors as adjuvants that exploit weaknesses in metal homeostasis processes when cells are under drug stress. A combination of checkerboard growth assays and whole-cell metal analysis has revealed remarkable synergistic activity of select agents against C. albicans. Importantly, data collected from proteomic mass spectrometry methods and biochemical assays have provided mechanistic insights into the cellular targets of these agents, revealing the strong interconnection between copper regulation and oxidative stress pathways.