There are many important new advances in the development of clinically viable therapeutic options to mitigate the pathophysiology of sickle cell disease (SCD). Some of the most promising new clinical candidates reported herein directly address the primary cause of the disease by allosterically modifying sickle hemoglobin (HbS). In particular, one family of small molecules stabilizes the high oxygen (O₂)-affinity R-state of the protein, which, unlike the low O₂-affinity T-state, does not present the polymerization promoting βVal6 residue. Several compounds employing this mechanism are currently at various stages of preclinical and clinical investigations. Another series of compounds that engage in a covalent bond with the surface-located residue βCys93 of HbS, and thus destabilize the T-state to increase Hb affinity for oxygen, is currently under preclinical development. Furthermore, promising new compounds that, similar to hydroxyurea also induce fetal Hb production, are at various stages of clinical development. Finally, compounds that target the secondary pathophysiology of SCD, including those that counter the dehydration of sickle erythrocyte; endothelial adhesion and vasculature damage; nitroxide donors providing vasodilatory and anti-inflammatory effects; and a myriad of anti-inflammatory and anticoagulation candidate molecules, are also being investigated in early- and/or late-stage clinical trials.