Sickle cell disease (SCD) is an inherited disorder prevalent in Sub-Saharan Africa, Middle East and parts of India. Its characterized by repetitive episodes of vaso-occlusive (VOC) process leading to recurrent painful episodes, hemolytic anemia and predisposition to infection. Sickle cell crises varies and this what brings patients to hospital including VOC leading to recurrent painful episodes, or organ specific complications such as acute chest syndrome, stroke, splenic sequestration, and many skeletal complications. Although the prognosis of patients with SCD has improved, however still these events contributes to decrease quality of life and increased risk of death. Also unfortunately, progress on the management of these acute complications is slow, and tended to be supportive including vaccination, use of antibiotics prophylaxis and blood transfusions. Better understanding of pathophysiology of the disease has allowed more accelerated progress on preventing these complications and development of more focused pharmacological therapies. Hemoglobin polymerization is a primary triggering event in the pathophysiology of the disease, leading to the sickling process, this usually ignite an inflammatory process/tissue ischemia and increased adhesions. This understanding of the pathophysiology has allowed scientist to develop drugs that interfere with these processes such as Voxeletor & Hydroxyurea (interfere with polymerization-both approved by FDA), l-glutamine and Omega 3 (interfere with inflammatory process and oxidative stress) and crizanlizumab and Tinzaparin (works by inhibiting adhesion molecules). This will allow patients and physicians the freedom for a number of therapeutic interventions including development of combinations protocols. SCD is very complex and require a drug with multi-faceted action such as Hydroxyurea and this is of the limiting factors in the new recently approved drugs, limiting the patients who can benefit from each of them. Further progress is also seen in the area of bone marrow transplant (including alternative donor pool) and gene therapy/gene editing.