The evolution from ectotherm to endotherm with all the attendant genetic and structural modifications was the single most important biological event for the establishment of the hominoid species. A previous publication hypothesized that the appearance of small, enucleated red blood cells (RBCs) and platelets in mammals, reduced RBC size in birds, increased vascular density in all tissues, and the evolution of the four-chambered heart were required for the evolution of avian and mammalian endothermy. The genetic and structural changes in birds and mammals were initiated by the selective pressure of low atmospheric oxygen during the Permian period and ultimately led to endothermy . The establishment of endothermy in mammals and birds afforded animals a more efficient cardiovascular system to exchange O2 for metabolically produced CO2 in their tissues than occurs in ectotherms. This permitted mammals to maintain: their body temperature in expanded environmental niches; a constant energy production with optimized enzyme activity that could facilitate the flight-or-fight response; lactation for off-spring; and increased brain size, to name a few advantages. A better understanding of the molecular events that led to endothermy would add much to our understanding of many diseased states and would facilitate the development of targeted drugs for their treatment.