The regulation and maintenance of systemic iron homeostasis is critical to human health. Iron overload and deficiency diseases belong to the most common nutrition-related pathologies across the globe. It is now well appreciated that the hormonal hepcidin/ferroportin system plays an important regulatory role for systemic iron metabolism. We review recent data that uncover the importance of the cellular iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network in systemic iron homeostasis. We also discuss how the IRE/IRP regulatory system communicates with the hepcidin/ferroportin system to connect the control networks for systemic and cellular iron balance.