Decreasing HbS by increasing HbA or HbF is a primary therapeutic focus for sickle cell disease (SCD). Current disease-modifying therapies, such as RBC transfusions and hydroxyurea (HU), are mainstays but do not fully eliminate complications. Transfusions afford replacement with red blood cells that carry HbA, while HU stimulates HbF with high person-to-person variability. Other therapies targeting other downstream effects may lead to symptom control but fail to eliminate disease complications. The optimal strategy must be universally applicable and effective, and may be achieved by targeting the underlying genetic basis to produce sufficient HbA or HbF in a pancellular distribution. Replacement or repair of autologous patient hematopoietic stem cells (HSCs) through allogeneic transplantation (alloHCT) or genetic modification, respectively, represents a potential cure. AlloHCT has been available as a curative option since 1984, but its use is limited by the rarity of well-matched donors and the risk of immunological complications. Recently, autologous HSC-based genetic therapies have emerged as promising alternatives. These approaches include genome editing strategies of key regulatory elements for HbF induction in RBCs. Despite their potential, these ex vivo genetic modification strategies present significant technical, logistical, and financial challenges, including limited HSC collection, high cell loss during cell selection, and membrane damage from electroporation. Advancing and simplifying these genome editing approaches remain essential to the continued development of curative therapies for SCD.