This manuscript deals with why we need alternatives to liquid stored RBC highlighting some of the unresolved inherent problems related to red cell storage lesion and their potential impacts on the clinical outcomes and transfusion complications. The promise of several potential alternatives to red cell transfusions such as: Perfluorocarbon; Modified Hb-based oxygen carriers and newer design of Hb-based oxygen carriers are reviewed. It is noteworthy to say that since the first introduction of these oxygen carriers, almost five decades ago, the only successful drive has been to prepare safer and more convenient oxygen carriers, for enhancing the quality of life of recipients and their usage, either as substitutes to red cell transfusion or even as the bridge, remains patchy. Moreover, as new products with better characteristics become available the older products from the competitors are withdrawn. Finally, the current progress on universal RBC, known as ECO-cells is highlighted and, in the future perspectives, some of the current efforts in making the red cells transfusion safer and more efficacious are briefly addressed.