Publisher Summary This chapter presents a discussion on the evolution of protoaerobic and aerobic prokaryote chemotypes. The evolution of prokaryotes is more in oxidizing environments. The chapter describes the chemistry developed for the protection of the prokaryote cytoplasm from O2 and H2O2 and then explains the first uses of oxidized elements—S, Fe, N. The major evolutionary developments in prokaryotes, taking all prokaryote chemotypes together as part of the total ecosystem of all living organisms are one part of the total ecosystem, took place before eukaryotes appeared. The features and activities are controlled in each cell so that each is part of a total organization of internal genes, proteins, metabolism, and metal ions. The environment are linked and limited in autocatalytic pathways. The major drives in all the changes are simultaneously greater energy intake, greater biomass, greater degradation rate of organic chemicals, and a resultant greater rate of heat, thermal entropy production. However, a major failure was the unavoidable poor use of space, with a rather inflexible membrane and low level of total organization leaving the possibility for larger organisms to appear in evolution. Finally, the prokaryotes were unable to digest large molecules and particles of food except externally.