Hematopoietic stem cell transplantation (HSCT) is the only established curative treatment for sickle cell disease (SCD), a debilitating red blood cell (RBC) disorder with significant prevalence worldwide. Accurate assessment of RBC engraftment following HSCT is essential to evaluate the status of the graft and can enable early intervention to treat or prevent graft rejection. Currently, chimerism measurement is performed on whole blood samples, which mainly reflect white blood cell (WBC) chimerism. This approach has limitations in assessing engraftment in patients with SCD because RBCs engraft non‐linearly with WBCs. Direct measures of RBC chimerism exist but are not routinely used. In this review, we critically examine the current methodologies for assessing donor engraftment; highlight the limitations of these different methods, and present emerging and novel technologies with the potential to improve clinical monitoring of RBC engraftment post‐HSCT for SCD. Promising alternative methodologies include RBC‐specific flow cytometry, RBC‐specific RNA analysis, and quantification of plasma cell‐free DNA derived specifically from nucleated RBCs.