Whereas RBC transfusion therapy is lifesaving in thalassemia, obligatory iron loading accompanies such treatment and chelation therapy to remove and detoxify iron resulting from these chronic transfusions must therefore be administered. Morbidity and mortality in thalassemia is linked closely to the adequacy of chelation. Three chelators are currently available worldwide—deferoxamine, deferasirox, and deferiprone, although the latter is available in North America only in research protocols and compassionate use programs. These chelators can be used as monotherapy or in combination, although only the combination of deferiprone and deferoxamine has been extensively studied to date. Several factors, including chelator availability and its properties, drug tolerability, degree of organ-specific iron loading, ongoing transfusional iron burden, and patient preference, must be considered in the design of optimal, individualized chelation regimens, and these factors must periodically be reviewed and chelation adjusted accordingly. Ultimately, comparative effectiveness trials may help to determine the ideal strategy (eg, intensification of monotherapy or combined therapy including agents and doses) for treating various scenarios of organ-specific iron loading.