OBJECTIVE We used the methods of yeast genetics to identify genes involved in acquisition of iron by eukaryotic cells. METHODS Mutants were identified with defects in cellular iron uptake. These were organized into an upstream group and a downstream group. The upstream group was involved in the delivery of copper to the multicopper oxidase FET3. Mutants of this group were characterized by defective iron uptake that could be corrected by exposure of the cells to large amounts of copper. The downstream group was more directly involved in iron uptake. Mutant phenotypes from these genes could not be corrected by copper exposure. RESULTS Genes in the upstream group encoded the regulator of copper transport, MAC1, and two copper transporters, CTR1 and CCC2. Genes in the downstream group encoded the multicopper oxidase FET3 and its partner the iron permease FTR1. In addition, the downstream genes encoded the surface reductases FRE1 and FRE2 and the iron regulatory protein AFT1. CONCLUSIONS The iron and copper uptake processes in yeast intersect because the FET3 gene encodes a multicopper oxidase that is required for iron transport. In human beings, an analogous function may be served by ceruloplasmin, a multicopper oxidase with a role in iron homeostasis.