Extracellular levels of adenosine increase in response to hypoxia (see Figure 1). Elevated adenosine activates ADORA2B adenosine receptors on erythrocytes, thereby activating downstream signaling pathways resulting in increased intracellular 2,3-bisphosphoglycerate (2,3-BPG), an allosteric regulator of hemoglobin (Hb) that reduces oxygen-binding affinity. This signaling pathway is beneficial to for normal individuals leading to increased oxygen release to hypoxic tissues. However, this process is detrimental for individuals with sickle cell disease by promoting the release of oxygen from sickle hemoglobin (HbS), resulting in increased concentrations of deoxy-HbS, increased deoxy-HbS polymerization and sickling.