The American Society for Apheresis (ASFA) conducted a one-day consensus conference on red blood cell exchange (RBCx) in sickle cell disease (SCD) during its annual meeting in San Antonio, TX, on May 5, 2015. The authors of this article, a subcommittee of ASFA’s Clinical Applications Committee, developed several questions with regard to pathophysiology of SCD and use of RBCx in the management of various complications. These questions were provided to the seven invited speakers who are the experts in the field of SCD. Two experts in the field moderated the proceedings of the conference, which was attended by more than 150 participants. After each presentation, there was a summary of the main points by the moderators and an open discussion with questions from the audience. A video recording of the proceedings, as well as each presentation, was made available to the authors. Each author’s summary was reviewed and approved by the respective speaker before submission of this manuscript. The subcommittee also developed several key questions to generate a consensus amongst the speakers on key issues for using RBCx for patients with SCD.