Mammalian iron homeostasis is maintained through the concerted action of sensory and regulatory networks that modulate the expression of proteins of iron metabolism at the transcriptional and/or post-transcriptional levels. Regulation of gene transcription provides critical developmental, cell cycle, and cell-type-specific controls on iron metabolism. Post-transcriptional control through the action of iron regulatory protein 1 (IRP1) and IRP2 coordinate the use of messenger RNA-encoding proteins that are involved in the uptake, storage, and use of iron in all cells of the body. IRPs may also provide a link between iron availability and cellular citrate use. Multiple factors, including iron, nitric oxide, oxidative stress, phosphorylation, and hypoxia/reoxygenation, influence IRP function. Recent evidence indicates that there is diversity in the function of the IRP system with respect to the response of specific IRPs to the same effector, as well as the selectivity with which IRPs modulate the use of specific messenger RNA.