Fig. 1. Advances in ex vivo T cell-depleted haploidentical hematopoietic stem cell transplantation. The ex vivo techniques to remove T cells have evolved from the selection of CD34⁺ hematopoietic stem cell progenitors to the depletion of CD3⁺ cells, and more recently, the depletion of αβ⁺ T cells. Early attempts with haploidentical HSCT using CD34-selected stem cells, even with a megadose, were complicated by a high rate of infections likely related to delayed immune recovery. To overcome the limitation of CD34⁺ selection, the concept of direct depletion of T cells using anti-CD3 monoclonal antibody was introduced with the advantage of increasing the number of natural killer (NK) cells, and other immunomodulating cells. Depleting CD3⁺ cells was superior to selecting CD34⁺ cells in terms of engraftment speed and immune reconstitution. Although haploidentical HSCT using CD3-depleted grafts successfully reduce lethal infection rates, delayed immune recovery and the high rate of relapse were still problematic. The most recently developed approach using the negative depletion of αβ⁺ T cells improved the outcomes of T cell-depleted haploidentical transplant. Although recent advances in haploidentical HSCT, delayed immune reconstitution with subsequent infections and relapse for malignant disease are current major causes of treatment failure. New depletion technique to deplete naïve T cells or adoptive transfer of immune effector cells and cellular therapy based on γδ T cells or other immune cells could further improve the outcomes of haploidetical HSCT.