Sickle cell disease (SCD) refers to a group of inherited blood disorders that occur because of a point mutation in the HBB gene, producing pathologic, abnormal sickle hemoglobin (HbS). Under low oxygen conditions, HbS polymerizes into intracellular fibers, causing the red blood cell (RBC) to sickle, and alters RBC function. RBC sickling, cell dehydration, and inflammatory processes alter many hemorheological parameters, including (1) whole blood viscosity, RBC (2) deformability, (3) adhesion, and RBC density, all of which are associated with acute and chronic disease complications and overall disease severity. However, currently used clinical biomarkers such as %HbF or markers of hemolysis fail to provide a complete picture of RBC function. Current assays that measure these hemorheological parameters include viscometry (whole blood viscosity), oxygen gradient ektacytometry (deformability), and automated hematology analyzers (dense RBC fractions). Emerging microfluidic platforms are also being developed to offer lower-cost, portable alternatives that can functionally assess RBC deformability and adhesion. These techniques have recently gained popularity as clinical trial outcome measures and inclusion criteria. However, the widespread adoption of these tools in trials and in routine patient care remains limited. Here, we describe the current and proposed use of RBC function testing assays and their existing clinical validation.