ABSTRACTCopper is an essential nutrient that is toxic to cells when present in excess. The fungal pathogenCandida albicansemploys several mechanisms to survive in the presence of excess copper, but the molecular pathways that govern these responses are not completely understood. We report that deletion ofGPA2, which specifies a G-protein α subunit, confers increased resistance to excess copper and propose that the increased resistance is due to a combination of decreased copper uptake and an increase in copper chelation by metallothioneins. This is supported by our observations that agpa2Δ/Δ mutant has reduced expression of the copper uptake genes,CTR1andFRE7, and a marked decrease in copper accumulation following exposure to high copper levels. Furthermore, deletion ofGPA2results in an increased expression of the copper metallothionein gene,CRD2. Gpa2p functions upstream in the cyclic AMP (cAMP)-protein kinase A (PKA) pathway to govern hyphal morphogenesis. The copper resistance phenotype of thegpa2Δ/Δ mutant can be reversed by artificially increasing the intracellular concentration of cAMP. These results provide evidence for a novel role of the PKA pathway in regulation of copper homeostasis. Furthermore, the connection between the PKA pathway and copper homeostasis appears to be conserved in the pathogenCryptococcus neoformansbut not in the nonpathogenicSaccharomyces cerevisiae.