Recent years have witnessed an explosion in the breadth of investigations on transition metal homeostasis and the subsequent depth of our understanding of metals in biology. Many genes and proteins that serve in the uptake, distribution, sensing and detoxification of one such transition metal, copper, have been identified. Through genetic and biochemical studies, the molecular details of copper uptake are being elucidated, and evidence suggests a largely conserved mechanism for copper acquisition and distribution from yeast to humans. Investigations of the mitochondrial copper pathway reveal the complexity surrounding copper delivery to cytochrome oxidase and highlight additional roles for some of the participants in copper homeostasis, such as a copper chaperone that influences the subcellular distribution of its target for copper incorporation. Furthermore, our understanding of the structure and function of copper transporters, chaperones and cupro-proteins, coupled with the emergence of additional model systems, is providing surprising examples of the integration of copper homeostasis with other physiological and pathophysiological processes and states, such as cancer, aging and virulence.