The vast knowledge of the physiologic functions of zinc in at least 3000 proteins and the recent recognition of fundamental regulatory functions of zinc(II) ions released from cells or within cells links this nutritionally essential metal ion to numerous diseases. However, this knowledge so far has had remarkably limited impact on diagnosing, preventing, and treating human diseases. One major roadblock is a lack of suitable biomarkers that would detect changes in cellular zinc metabolism and relate them to specific disease outcomes. It is not only the right amount of zinc in the diet that maintains health. At least as important is the proper functioning of the dozens of proteins that control cellular zinc homeostasis, regulate intracellular traffic of zinc between the cytosol and vesicles/organelles, and determine the fluctuations of signaling zinc(II) ions. Cellular zinc deficiencies or overloads, a term referring to zinc concentrations exceeding the cellular zinc buffering capacity, compromise the redox balance. Zinc supplementation may not readily remedy zinc deficiency if other factors limit the capability of a cell to control zinc. The role of zinc in human diseases requires a general understanding of the wide spectrum of functions of zinc, how zinc is controlled, how it interacts with the metabolism of other metal ions, in particular copper and iron, and how perturbation of specific zinc-dependent molecular processes causes disease and influences the progression of disease.