There is an enormous demand for blood transfusions in daily clinical practices since blood products, especially red blood cells (RBCs), can significantly improve survival. However, donor-derived RBCs have important limitations as a result of their insufficient availability, the need for typing and cross-matching, short shelf-life or risk of pathogenic contamination. Thus, as a result of the unique oxygen-transport ability of hemoglobin (Hb), Hb-based oxygen carriers (HBOCs) have attracted a lot of attention for the development of RBC surrogates able to provide tissue oxygenation. Here, we highlight the progress in the development of HBOCs, focusing on different examples that have undergone exhaustive pre-clinical and clinical evaluation. In addition, we also provide a comprehensive review of very recent and innovative examples to aid in the development of the next generation of blood substitutes.