In biological systems, iron exerts 2 contrasting effects. The chemical reactivity of iron is essential for the biological activities of proteins such as hemoglobin, ribonucleotide reductase, the cytochromes, and aconitases. However, free iron in a cell has the propensity to generate free radicals which can damage cellular components containing proteins, lipids, and nucleic acids. To maintain the balance between iron as an essential nutrient and iron as a potential cytotoxin, a number of biological protective mechanisms have evolved. As shown in the thalassemias, iron imbalance can have devastating effects on human health. Recently, several new proteins have been described that play critical roles in iron regulation including the master regulator of iron metabolism (hepcidin). In this review, we discuss the new knowledge that has arisen from studies in yeast and in humans, and we show how these studies are shedding new light on some well-known human disorders.