Beta-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. The generation of lentiviral vectors (LVs) carrying a β-globin-like gene has revolutionized this field by allowing effective HSC transduction with no evidence of genotoxicity to date. Several clinical trials with different kinds of vector are underway worldwide; the initial results are promising with regard to sustained production of therapeutic hemoglobin, improved biological parameters, lower transfusion requirement and better quality of life. Long-term follow-up will confirm the safety of this LV-based gene therapy. Optimization of patient conditioning, HSC harvest and transduction process further improved the therapeutic potential of this approach. Novel LV-based strategies aiming at 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 to reactivate HbF are currently under investigation. Here, we discuss the clinical outcomes of current LV-based gene addition trials and the potential advantages of novel alternative therapeutic strategies.