Sickle cell disease (SCD), a globally prevalent health issue, results from a genetic mutation leading to the production of abnormal haemoglobin. Despite being a monogenic disorder, SCD exhibits diverse phenotypic expressions influenced by various genetic polymorphisms, which affect treatment responses. Hydroxyurea (HU) is the primary Food and Drug Administration (FDA)-approved therapy for SCD, but patient responses vary considerably due to genomic variation. Vaso-occlusive crises, common in SCD, often require prolonged analgesia and HU use, raising safety and management concerns. The SickleInAfrica initiative, comprising Sickle Cell Pan African Network (SPAN), Sickle Africa Data Coordinating Centre (SADaCC), and Sickle Pan-African Research Consortium (SPARCO), aims to explore genetic variants in African SCD populations. Various studies, including large-scale investigation and bioinformatics initiatives in Africa, contribute to understanding the genetic basis of SCD phenotypes. The SickleInAfrica registry facilitates collaborative data collection across sub-Saharan Africa, addressing ethical considerations. Despite these initiatives, pharmacogenomics of SCD treatments remains limited in Africa. This underscores the need for further research on genetic markers influencing treatment efficacy and the risk of complications.