Disorders of iron homeostasis, resulting in iron deficiency or overload, are very common worldwide (1). Normal iron homeostasis depends on a close link between dietary iron absorption and body iron needs (2). The paper by Nicolas et al. in this issue of PNAS (3) presents the exciting possibility that a central player in the communication of body iron stores to the intestinal absorptive cells may have been identified. This unlikely player, originally identified as a circulating antimicrobial peptide, is the hepatic protein hepcidin. Nicolas et al. found absence of hepcidin expression in mice exhibiting iron overload consequent to targeted disruption of the gene encoding the transcription factor Upstream Stimulatory Factor 2 (USF2). Nicolas et al. present the exciting possibility that a central player in the communication of body iron stores to the intestinal absorptive cells may have been identified.