Many children with sickle cell disease are severely affected by acute complications, especially stroke, recurrent and debilitating pain, or recurrent acute chest syndrome. As they become adolescents and young adults, patients with sickle cell disease often develop chronic problems, including renal disease, chronic lung disease and pulmonary hypertension. For children who have an HLA matched related donor, a hematopoietic stem cell transplant (HSCT), using bone marrow or cord blood is an effective cure; using the standard approach, which relies on high doses of busulfan (BU) and cyclophosphamide (CY) as well as anti-thymocyte globulin (ATG) for pre-transplant conditioning, the probability of event free survival is now approximately 95%. The standard approach, however, is frequently complicated by acute and often severe neurological events, such as seizure and encephalopathy, as well as hypogonadism. Circumstantial evidence suggests that sickle cell patients are predisposed to transplant related neurological toxicities by disease related cerebrovascular injury, and that the transplant process aggravates this injury, causing cerebral ischemia and, in turn, neurological toxicity. The high dose chemotherapy, which has been shown to induce endothelial injury, appears to be an important contributing factor. The role of high dose chemotherapy in transplant related neurotoxicity needs to be more firmly established. The role of high dose alkylating agents in gonadal injury has been well established. Fludarabine, a non-vasculopathic, non-gonadotoxic agent, amplifies the engraftment promoting effects of Cy; in an effort to lessen the incidence of transplant related neurotoxicity and gonadotoxicity, we will conduct a pilot study in which fludarabine is added to BuCyATG for conditioning, and the dose of Bu and Cy are reduced using a stepwise de-escalation schema. This study will serve as a forerunner to larger trial designed to test the safety and efficacy of a reduced toxicity BuFluCyATG regimen. Central Hypothesis: A safer approach to hematopoietic stem cell transplantation (HSCT) can be developed for children with sickle cell disease without compromising efficacy. Specific Aims: 1) To begin to develop a reduced dose busulfan and cyclophosphamide based conditioning regimen for children with sickle cell disease that still achieves sustained engraftment at least 90% of the time, by conducting a pilot trial, in which the standard busulfan, cyclophosphamide and anti-thymocyte globulin conditioning regimen is modified by adding fludarabine, a non-vasculopathic and non-gonadotoxic, yet highly immunosuppressive agent, in order to determine the feasibility of reducing the total dose of cyclophosphamide from its present standard of 200 mg/kg to 90 mg/kg and the busulfan from its present standard of 12.8 mg/kg (IV) to 6.4 mg/kg, using a four step dose de-escalation schema.. 2) a) To begin to assess the vascular, and more specifically, the cerebrovascular effects of pre-transplant, high-dose busulfan and cyclophosphamide in children with sickle cell disease by obtaining preliminary estimates of longitudinal changes in the blood levels biomarkers of endothelial dysfunction and inflammation (endothelin-1, von Willebrand factor antigen, C-reactive protein, Il-8 thrombin-antithrombin (TAT) complexes) and in the changes in two MRI biomarkers-cortical thickness measurement and diffusion tensor imaging.. b) To begin to assess the long-term effects of replacing sickle erythrocytes with normal erythrocytes (by HSCT) on the vasculature and cerebrovasculature, using the same tests. These estimates will help us to calculate a sample size and refine our testing for the second study.