This review paper aims to present an overview of the development of blood substitute particularly red blood cell substitute or artificial oxygen carrier. Knowledge on human blood inspired from the understanding of human blood circulation system. Ibn Nafis was first to describe that blood flow through respiratory system before entering the heart. This finding denied the claim that tiny pores present within the septum of the heart. Then, William Harvey further described human cardiovascular system in detail and contributed to better understanding on the roles of blood in body. Several blood transfusions were attempted using blood collected from human, animal and other blood substitutes such as milk before the practice was banned for almost 150 years in Europe. Major discoveries on blood group and antibody reaction have made blood transfusion safer. However, several issues and challenges have re-triggered the exploration to develop red cell substitutes. Two approaches have been taken to develop the red blood cell substitute which are classified into biological and chemical based oxygen carriers. The earliest efforts have been on haemoglobin based oxygen carrier (HBOC) and perfluorocarbon (PFC) while the recent developement are on polymer-based oxygen carrier and in-vitro stem cell derived red blood cell.