Although the existence of abnormal cation and water loss in sickled red cells has been well-described, upstream regulation of this loss has been incompletely understood. Furthermore, microRNA regulation in mature red cells has recently been described, and its dysregulation in sickled red cells affects their tolerance of oxidative stress. In this session, the central role of newly discovered red cell channels and their advantage as a therapeutic target compared to Gardos channel blockers (which failed to reach their endpoint in clinical trials) will be described. Also, microRNA dysregulation as a potential therapeutic target will be discussed.