Background : Several circumstances such as accidents, surgery, traumatic hemorrhagic shock, and other causalities cause major blood loss. Allogenic blood transfusion can be resuscitative for such conditions; however, it has numerous ambivalent effects, including supply shortage, needs for more time, cost for blood grouping, the possibility of spreading an infection, and short shelf-life. Hypoxia or ischemia causes heart failure, neurological problems, and organ damage in many patients. To address this emergent medical need for resuscitation and to treat hypoxic conditions as well as to enhance oxygen transportation , researchers aspire to achieve a robust technology aimed to develop safe and feasible red blood cell substitutes for effective oxygen transport. Area covered in This review article provides an overview of the formulation, storage, shelf-life, clinical application, side effects, and current perspectives of artificial oxygen carriers (AOCs) as red blood cell substitutes. Moreover, the pre-clinical (in vitro and in vivo) assessments for the evaluation of the efficacy and safety of oxygen transport through AOCs are key considerations in this study. With the most significant technologies, hemoglobin- and perfluorocarbon-based oxygen carriers as well as other modern technologies, such as synthetically produced porphyrin-based AOCs and oxygen-carrying micro\nanobubbles, have also been elucidated. HISTORY 1. William Harvey discovered blood pathways in 1616 .Many people tried to use fluids such as beer, urine, milk and animal blood as a blood substitute.[1] 2. The first approved oxygen carrying blood substitute was a Per fluorocarbon based product called Fluosol-DA-20 .Manufactured by Green cross of Japan. It was approved by the food and drug administration in 1989.[2] 3. In 1990’s Haemoglobin based oxygen carriers called Haemopure was approved for phase-3 trail.[3] 4. In December 2003 new Haemoglobin based oxygen therapeutic called Polyheme was introduced.[4,5]