Paradoxically, iron can be highly toxic when allowed to accumulate in excess. Indeed, high concentrations of iron have the potential to produce toxic hydroxyl radicals through the Fenton reaction. These two facets of iron properties require that organisms must sense their internal iron load and respond appropriately by regulating iron acquisition, thereby keeping iron concentrations under tight control. Studies using the yeast model Schizosaccharomyces pombe have allowed discovery of genes encoding proteins that function in the regulation of iron homeostasis. The GATA-type transcription factor Fep1 represses several genes involved in iron acquisition when iron levels are high. A second iron-responsive factor, denoted Php4, is critical for down-regulating genes encoding ironusing proteins when iron levels are low. Php4 is a subunit of the CCAAT-binding protein complex. In response to iron starvation, Php4 is synthesized and interacts with the Php2/ Php3/Php5 heterotrimer to repress genes that encode components of iron-requiring metabolic pathways, such as the tricarboxylic acid cycle, the electron transport chain, and the iron-sulfur cluster biogenesis machinery. CGFS-type monothiol glutaredoxins are classified into two groups. The first group is composed of single-domain CGFS monothiol glutaredoxins involved in iron-sulfur protein biogenesis and maturation. The second group consists of multidomain CGFS monothiol glutaredoxins. These glutaredoxins deliver and transfer iron-sulfur clusters to proteins and subcellular compartments. In addition, they sense and communicate cellular iron status to iron-responsive transcription factors. Recent studies have suggested that the TRX domain serves as a docking site for interacting partners of multidomain CGFS monothiol glutaredoxins. The GRX domain of Grx4 contains a typical 172CGFS175 active site motif. The CGFS-type monothiol glutaredoxins can form -bridged homodimers. The combination of two GRX domains generates two Cys ligands to which a cluster can be coordinated with the aid of two glutathione molecules that provide the other two cluster ligands. This complex results in a glutathione-ligated center that is held within the monothiol glutaredoxin dimer. Inactivation of the grx4+ gene makes a constitutively active Fep1 that binds to its target gene promoters in vivo. In the absence of Grx4, Fep1 behaves like an insensitive protein, constitutively repressing target gene expression. Although the molecular basis by which Grx4 communicates iron deficiency to Fep1 remains obscure, twohybrid and coimmunoprecipitation experiments have revealed that the TRX domain of Grx4 associates strongly and constitutively with the C-terminal region of Fep1. Subsequent analyses have shown that, under low but not high iron conditions, the GRX domain of Grx4 associates with the N-terminal region of Fep1, which contains its DNA-binding domain.