Erythropoiesis is a process by which red blood cells (RBCs) are produced in the adult bone marrow. It involves the differentiation of erythroid progenitor cells into mature RBCs, which transport oxygen from the lungs to all cells in the body. Erythropoiesis is a complex process with a nuanced crosstalk of regulation involving hormones, cytokines, and growth factors. In recent years, multiple sources of evidence have increased our understanding of the molecular mechanisms that coordinate erythropoiesis to enable the daily production of approximately 200 billion RBCs. These advances have shed light on the pathophysiology in a variety of diseases, i.e., iron-loading anemias, and are paving the way for novel therapeutic strategies in preclinical and clinical development to treat such dyserythropoietic disorders. This chapter elucidates our current understanding of iron-loading anemias in general and specifically in β-thalassemia and myelodysplastic syndrome (MDS), describes the current cutting-edge understanding in pathophysiology, and delineates what novel therapies are currently being developed to target these disorders.