The improvement in survival and quality of life of iron-overloaded patients achieved by regular subcutaneous chelation has been extensively documented over the years. A review of the long-term results allows one to establish the following points: (1) with regular subcutaneous chelation, a negative iron balance can be obtained in most patients, except very young ones; (2) severe deferoxamine (DFO) toxicity may be prevented by skipping high doses and by carefully monitoring and modulating chelation, especially in patients with a low iron overload; (3) the maintenance of compliance with DFO over 0.6 and of ferritin levels below 2,000 prevents iron overloaded complications, at least for the first 20 years of life; (4) long-term chelation can reverse functional complications such as liver fibrosis, arrhythmia and echocardiographic abnormalities, but not complications due to extensive tissue alterations, such as frank diabetes, hypothyroidism and myocardiosclerosis; (5) intensive intravenous protocols can be successfully applied in heavily overloaded patients and represent the only possibility to reverse their dangerous iron burden in a relatively short period of time; (6) survival and quality of life in well-chelated patients are approaching a normal pattern, and (7) clinical outcome and prognosis are better evaluated by parameters that consider iron overload and chelation trends.