Sickle cell disease (SCD) is a severe genetic disorder caused by a single mutation in the β-globin (HBB) gene, leading to the production of sickle hemoglobin (HbS) and resulting in vaso-occlusion, chronic anemia, and organ damage. Gene editing, especially CRISPR/Cas-based approaches, offers potential cures of SCD by either reactivating fetal hemoglobin (HbF) or correcting the pathogenic HBB mutation in hematopoietic stem and progenitor cells (HSPCs). The recent FDA approval of exagamglogene autotemcel (exa-cel), an ex vivo CRISPR/Cas9-based gene-editing therapy targeting the BCL11A erythroid-specific enhancer for HbF induction, represents a breakthrough in SCD treatment. In addition to gene editing mediated by DNA double-strand break, base editing and prime editing offer potentially safer therapies. Despite these advances, there are safety concerns due to detrimental on- and off-target editing, and widespread implementation of ex vivo gene-editing therapy is limited by the high cost. In vivo gene editing, which modifies HSPCs directly in the body, presents an attractive alternative, but requires highly efficient and specific in vivo delivery. This review summarizes the therapeutic gene-editing strategies developed to date, elucidates the safety concerns, and discusses the opportunities and challenges in further developing gene-editing therapy of SCD.