Adult human hemoglobin (herein referred to simply as Hb) plays a crucial role in various physiological functions, with oxygen transport being the primary function. However, Hb is also central to one of the most common and debilitating inherited hematological disorder: sickle cell anemia or sickle cell disease (SCD). The disease arises from a single point mutation in the β-globin gene of Hb, substituting βGlu6 in normal Hb (HbA) with βVal6 in sickle Hb (HbS). This mutation leads to polymerization of HbS when deoxygenated, causing red blood cells (RBCs) to become rigid and adopt a characteristic sickle shape, leading to several pathological complications, including hemolysis, anemia, inflammation, vaso-occlusive crises, organ damage, and premature death. Despite the fact that SCD was the first disease to have its molecular basis established, and Hb, one of the first proteins whose atomic structure was elucidated, there remains an unmet need for disease-alleviating drugs; and chronic disease-alleviating oral therapy remains the holy grail for most patients. Given Hb’s central role in the SCD pathophysiology, it has become a key target for drug discovery efforts to treat the disease. This chapter examines noncovalent and covalent therapeutic strategies for targeting Hb, highlighting the discovery of 5-HMF, Voxelotor, Osivelotor, PF-07059013, and VZHE-039 for SCD treatment.