Thalassemia syndromes are a group of inherited hemoglobin disorders characterized by unbalanced globin-chain accumulation, ineffective erythropoiesis, chronic anemia, increased intestinal iron absorption, and consequent multi-morbidity. Thalassemic disorders are distinguished into transfusion-dependent thalassemia (TDT; regular lifelong blood transfusions starting before the age of 2 years) and non-transfusion-dependent thalassemia (NTDT; occasional blood transfusions or limited periods of transfusion). The only current curative therapy for TDT is hematopoietic stem cell transplantation, but this is only available for a minority of patients. Transfusion therapy can correct the anemia and reduce ineffective erythropoiesis but can lead to iron overload in the absence of appropriate iron chelation therapy with resulting multi-organ toxicity. In NTDT, even in the absence of regular transfusions, iron overload can occur due to the enhanced intestinal absorption that is secondary to ineffective erythropoiesis and hepcidin suppression, even if at a slower rate than in TDT. In this case-based review, we present how to manage iron overload in NTDT and TDT patients with currently available chelators. We also consider luspatercept, a new drug acting on erythropoiesis that has been developed and approved in TDT. Finally, we discuss a case of a young patient approaching allogeneic hematopoietic stem cell transplantation and which investigations and medical decisions should be taken to optimize possibilities of success.