Mythological stories from the Far East and the West have referenced the importance of metals and metalloids in numerous human activities ranging from farming, armor, archery and to use in medicine indicating their role and importance in human life. The era of industrial revolution brought to forefront the use of metals in industrial machines to household usage and ornaments. In the absence of recognition of potential health effects associated with exposure to metal or metal compounds, their contribution through occupational or environmental exposure in general population was largely ignored for long. It’s only in late 18th century that the importance of metal constituents in the biological processes has been recognized. The alkali (Na, K) and alkaline earth metals (Mg, Ca) play critical role in basic biological processes and ate required in larger quantities and therefore are suitably recognized as macronutrients. Nutritional, toxicological and genetic research over the past century has led to the recognition of the critical role micronutrients/transition metals (such as Fe, Cu, Mn, Zn) play in diverse cellular and molecular events. In the post genome era, characterization of various metal-binding and transport proteins revealed their role in intracellula, absorption, transport and storage of metals and their role in disease pathology. A coordinated interaction of these proteins is essential in the regulation of metal homeostasis mechanisms. An imbalance in the intracellular transition metal content (due to increased absorption from diet of malnutrition) can result in adverse effects. Recent research has also provided vital clues on the role of mutant transport proteins in genetic disorders such as hemochromotosis, thalassemia, Menkes and Wilson diseases.