β-Thalassemia and sickle cell disease (SCD) are the most prevalent monogenic diseases. These disorders are caused by quantitative or qualitative defects in the production of adult hemoglobin. Gene therapy is a potential treatment option for patients lacking an allogenic compatible hematopoietic stem cell (HSC) donor. New-generation lentiviral vectors (LVs) carrying a β-globin-like gene have revolutionized this field by allowing effective HSC transduction, with no evidence of genotoxicity to date. Several clinical trials with different types of vector are underway worldwide; the initial results are encouraging with regard to the sustained production of therapeutic hemoglobin, improved biological parameters, a lower transfusion requirement, and better quality of life. Long-term follow-up studies will confirm the safety of LV-based gene therapy. The optimization of patient conditioning, HSC harvesting, and HSC transduction has further improved the therapeutic potential of this approach. Novel LV-based strategies for reactivating endogenous fetal hemoglobin (HbF) are also promising, because elevated HbF levels can reduce the severity of both β-thalassemia and SCD. Lastly, genome-editing approaches designed to correct the disease-causing mutation or reactivate HbF are currently under investigation. Here, we discuss the clinical outcomes of current LV-based gene addition trials and the promising advantages of novel alternative therapeutic strategies.