This chapter focuses on the signaling pathways involved in the synthesis of hepcidin, the iron hormone, and discusses the pathophysiological consequences of genetic and nongenetic disruption of its regulation. Hepcidin acts as the principal physiological inhibitor of iron flux into the bloodstream by inhibiting its receptor, the iron exporter ferroportin. Hepcidin likely evolved to protect humans from excess iron, which favors pathogen growth or oxidant damage to vital organs. To do so, it senses iron, inflammatory, nutrient and stress signals and rapidly turns on its transcriptional machinery in response to distinct signaling pathways. However, whenever iron demand increases in the erythroid compartment, hepatic hepcidin transcription is readily repressed by bone marrow-derived factors so that more iron can enter the bloodstream to support the increased erythroid activity. Dissecting the regulatory mechanisms of hepcidin transcription in the liver has profoundly changed our view of human diseases associated with disturbances of iron homeostasis and opened the way for novel therapeutic applications.