Due to the continuously insufficient supply and the disadvantages associated with the donated blood, artificial blood substitute has received extensive attentions throughout the world in recent years. Nano-structured hemoglobin-based oxygen carriers (NHOC), which combine the nanotechnology with the traditional cellular oxygen carriers, exhibit excellent oxygen-carrying capacity, long blood circulation and unique tissue penetration/invasion property, and thus show great potential applications in blood transfusion, thrombus and cancer therapy as well. The present article reports on the current status of the research and application of the artificial blood substitutes with particular attention on NHOC. A general introduction on the history and characteristics of the artificial oxygen carriers is followed by the development of the liposome-encapsulated hemoglobin (LEH) and hemoglobin-based polymeric nanoparticels (HbPNPs). And then, attentions are devoted to highlight the main challenges of the NHOC: suppression of the methemoglobin formation and prolonging the blood circulation time. These results make us confident in advancing further development of NHOCs, with the expectation of their eventual commercialization.