Sickle cell disease (SCD) is a prevalent disorder resulting from a beta-globin gene mutation, causing the production of abnormal hemoglobin known as hemoglobin S. The disease can manifest with sickled cells, leading to hemolysis, anemia, painful episodes, organ damage, and potentially death. The timely identification of SCD is pivotal in diminishing mortality rates and facilitating effective disease management. Consequently, a variety of methodologies have been formulated to identify SCD and carrier states with elevated sensitivity and specificity. These methodologies encompass screening assessments such as complete blood count, peripheral blood smears, and the sickling test; confirmatory evaluations like hemoglobin separation techniques; and genetic examinations, which tend to be costlier and require execution in centralized laboratories by highly trained professionals. Nevertheless, innovative portable point-of-care (POC) methodologies have been established to offer an economical, straightforward, and user-friendly apparatus for the detection of SCD. Examples include the integration of solubility tests with portable devices, the application of smartphone microscopic classifications, image processing techniques, rapid immunoassays, and sensor-based platforms. This chapter elucidates the existing and new emerging strategies for the identification of SCD and underscores the various potential approaches that could be utilized to assist in the prompt diagnosis of SCD.