In Sub-Saharan Africa, high clinical demand for transfusion faces endemic bloodborne infections and limited resources. Blood screening for transfusion-transmitted bloodborne pathogens is the cornerstone of blood safety. Although there have been substantial improvements over the years, challenges in transfusion-transmitted infection screening that have been identified repeatedly long ago still need to be addressed. Affordability and sustainability of state-of-the-art quality assessed serological and molecular assays, and associated confirmation strategies remain of real concern. In addition, limited resources and infrastructures hamper the development of adequate facilities, quality management, and staff qualification, and exacerbate shortage of reagents and equipment maintenance. It is also important to maintain effort in constituting pools of repeat voluntary non-remunerated donors. Alternative strategies for blood screening that take into account local circumstances might be desirable but they should rely on appropriate field evaluation and careful economic assessment rather than dogma established from high-resource settings.