Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide with more than 300,000 babies in the world born every year with this disease. The clinical presentation and severity can be variable depending on many factors such as disease genotype, geographical location, environmental factors, and inheritance of other genetic abnormalities. The survival of patients with SCD have improved over last 3 decades where the expected median survival is more than 50 years for patients living in the developed countries. This improved survival is secondary to simple prophylactic and therapeutic interventions such as blood transfusions, prophylactic antibiotics, and vaccination. Disease modifying agents such as hydroxyurea contributed to the improved all disease outcome, survival, and quality of life. Over last 2 decades, curative options such as allogeneic stem cell transplant have gained popularity and increased evidence of safety and efficacy as the only curative option for SCD. However, there are many challenges to consider in patients who undergo hematopoietic stem cell transplantation (HSCT) that may affect the outcome. In this chapter, multiple challenges will be discussed including the indications of HSCT, choosing the appropriate donor and how to prevent and manage the unique or common post-transplant complications. Elaborative sections will focus on conditioning regimens choices in matched related donor HSCT. In addition, challenges in regards to various approaches of alternative donor transplant will be thoroughly discussed. Finally, long term effects and recommended follow up will be described.