Allogeneic stem cell transplantation is for a number of patients with malignant and nonmalignant diseases the only curative approach. For those patients who do not have an HLA-identical-related or -unrelated stem cell donor, a related three-loci mismatch haploidentical stem cell transplantation with T cell-depleted stem cells is a viable option. T cell depletion either by CD34(+) positive selection or by CD3-negative depletion strategies is available and has been investigated. We have shown that reduced-intensity conditioning haploidentical transplantation using mobilized peripheral stem cells negatively depleted from T and B lymphocytes is associated with a rapid immune reconstitution, a low transplant-related mortality rate, and a favorable outcome in patients in remission at the time of transplant. For chemorefractory patients, additional posttransplant cellular and humoral immunotherapeutic strategies are needed for prevention of relapse after transplantation.