The discovery of pathogenic nature of elevated plasma adenosine signaling via ADORA2B receptor activation in sickling reveals multiple innovative therapeutic targets for SCD. CD73-dependent elevated extracellular adenosine signaling via ADORA2B receptor in RBCs leads to activation of AMPK, subsequently increased BPG mutase activity, elevated 2,3-BPG production, and, eventually, increased deoxyHbS polymerization and sickling. Thus, CD73–ADORA2B–AMPK signaling cascades are innovative therapeutic targets to counteract sickling. ATP, adenosine triphosphate.