β-hemoglobin disorders, such as sickle cell disease (SCD) and β-thalassemia (BT), are the most common inherited monogenic blood disorders globally. Despite decades of research, there are only four FDA-approved medications available for the management of SCD with hydroxyurea (HU) being the most widely used drug that partially benefits patients by inducing fetal hemoglobin (HbF) production. On the other hand, there are no approved oral drugs currently available for β-thalassemia patients. To our knowledge, there are currently no well-characterized erythroid progenitor cell lines available that can accurately replicate the pathophysiology of SCD and BT while also having the same genetic background apart from the disease mutation enabling consistency and reproducibility. Our novel, physiologically relevant cellular systems provide a plethora of avenues for researchers to investigate various applications related to parasite invasion, drug validation, and genome-editing in the context of SCD and BT.