Sickle cell disease is one of the most common monogenic diseases in the world and, since its observation over 100 years ago, has become one of the most well-studied genetic diseases. The causal single point mutation in the beta-globin gene leads to the formation of hemoglobin polymers in the effected red blood cells under low oxygen conditions. While oral therapies are available to relieve some of the underlying symptoms, the only currently available cure is a hematopoietic stem cell transplant from a matched donor. However, most patients do not have an available donor and transplants carry the risk of rejection and immune complications. Therefore, gene therapy for sickle cell disease using a patient’s own hematopoietic stem cells offers the potential for a more viable treatment. The use of lentiviral vectors for gene therapy for the hemoglobinopathies has an established clinical course and several groups are currently in the midst of early trials. However, integrating vectors carry with them the risk for insertional oncogenesis as well as silencing or irregular expression of the transgene. Thus, targeted correction of the causal mutation would be an ideal approach for the treatment of sickle cell disease. Here we present data using targeted endonucleases in combination with a corrective donor template to induce targeted double-strand breaks in exon 1 of beta-globin and the subsequent repair of the break by homology directed repair in both cell lines as well as hematopoietic stem and progenitor cells. We describe the development of the reagents necessary to achieve this targeted correction, the optimization of delivery platforms for the nucleases as well as the donor template, and the refinement of the protocol for the treatment of CD34+ hematopoietic stem and progenitor cells. In addition, we demonstrate the ability of these nuclease and donor-modified cells to engraft an immunocompromised murine model and differentiate into multiple hematopoietic lineages. Finally, we show the correction of bone marrow hematopoietic stem and progenitor cells from sickle cell disease patients, resulting in the production of wild-type, adult hemoglobin tetramers. These data represent the foundational evidence for the site-specific gene correction of hematopoietic stem cells for sickle cell disease. We include a thorough description of the achievements made toward this aim as well as the remaining objectives and hurdles that face the genome editing field.