Iron can affect the clinical course of several chronic metabolic diseases such as type 2 diabetes, obesity, non-alcoholic fatty liver disease, and atherosclerosis. Iron overload can affect major tissues involved in glucose and lipid metabolism (pancreatic β cells, liver, muscle, and adipose tissue) and organs affected by chronic diabetic complications. Because iron is a potent pro-oxidant, fine-tuned control mechanisms have evolved to regulate entry, recycling, and loss of body iron. These mechanisms include the interplay of iron with transferrin, ferritin, insulin, and hepcidin, as well as with adipokines and proinflammatory molecules. An imbalance of these homoeostatic mechanisms results in systemic and parenchymal siderosis that contributes to organ damage (such as β-cell dysfunction, fibrosis in liver diseases, and atherosclerotic plaque growth and instability). Conversely, iron depletion can exert beneficial effects in patients with iron overload and even in healthy frequent blood donors. Regular assessment of iron balance should be recommended for patients with chronic metabolic diseases, and further research is needed to produce guidelines for the identification of patients who would benefit from iron depletion.