A viable blood substitute is still of great necessity throughout the world. Perfluorocarbon-based oxygen carriers (PFCOCs) are emulsions that take advantage of the high solubility of respiratory gases in perfluorocarbons (PFCs). Despite attractive characteristics, no PFCOC is currently approved for clinical uses. Some PFCOCs have failed due to secondary effects of the surfactants employed, like Fluosol DA, whereas others to adverse cerebrovascular effects on cardiopulmonary bypass, such as Oxygent. Further in-depth, rigorous work is needed to overcome the annotated failures and to obtain a safe PFCOC approved for human use. The aim of this study is to review in detail the most-used PFCOCs, their formulation, and preclinical and clinical trials, and to reflect upon causes of failure and strategies to overcome such failures.