The scarcity of blood for transfusion purposes has been widely acknowledged. Surgical therapeutic processes, war zones, and post-disaster treatments demand a huge amount of blood. Modern-day laboratories also require blood for bioengineering experimentation. Therefore, an artificially devised solution capable of mimicking the blood functions from biological and engineering relevance would be a noteworthy discovery of contemporary science. The experience drawn from discarded century-old blood substitutes has led us to technologically more advanced present-day solutions, which are better at carrying out the physiological functions of blood. Aiming at safety, stability, non-toxicity, and compatibility in terms of immuno-response, a remarkable number of substitutes are being tried to mimic the physiological properties and functions of red blood cells, platelets, plasma, and white blood cells. Despite significant efforts and time devoted, for transfusion, no product so far has been able to replace natural blood. This article puts together the important developments in blood substitutes that have evolved over the years, including substitutes for clinical as well as engineering requirements. It also points out the recent endeavors of synthesizing blood cells through modern synthetic routes. It has been highlighted that none of the blood substitutes have achieved the required efficacy so that they can be used . Finally, the emerging trends and future research needs have been stressed upon.