Iron overload in MDS starts even before patients become red-blood cell transfusion dependent, because disease-associated ineffective erythropoiesis suppresses hepcidin production in the liver and thus causes unrestrained iron absorption in the duodenum. However, the main cause of iron overload is regular transfusion therapy, which in MDS is associated with a risk of unclear magnitude for iron-related complications. Iron deposition in tissues can now be detected with non-invasive techniques such as T2* MRI. Iron toxicity in MDS may not only depend on the degree of tissue iron accumulation but also on the extent of chronic exposure to non-transferrin-bound iron (NTBI), including labile plasma iron (LPI) and intracellular labile iron pools, which increase the level of oxidative stress. Iron chelation therapy (ICT) can rapidly lower NTBI and LPI and more slowly mobilizes tissue iron stores. Further studies, including the ongoing TELESTO controlled trial, will more clearly define the role of ICT in MDS, including any effect on specific morbidities or mortality in the MDS setting.