Our approach to the study of metalloproteins is to engineer and fabricate peptide structures that incorporate metal cofactors toward the goal of generating molecular maquettes, protein-based synthetic analogues. Herein, we have analyzed all structurally characterized natural heme proteins to guide our design of synthetic heme protein maquettes for the investigation of the fundamental design principles of natural heme proteins involved in electron transfer reactions (the cytochromes) and dioxygen transport (the globins). Using heme protein maquettes, we have delineated the environmental factors which alter the heme reduction potential, a fundamental chemical property of natural cytochromes. By evaluating the coordination equilibria of ferric and ferrous heme to natural and synthetic protein scaffolds, we are providing fresh insight into the absolute (de)stabilization of these states by the protein environment The axial ligand σ-donor ability, porphyrin type, local electrostatic environment and heme burial all contribute to the modulation of the heme reduction potential over a 500 mV range. These dissociation constant and electrochemical data are used to discriminate between proton-coupled electron transfer (PCET) mechanisms in designed proteins. In addition, these data are used to develop a simple method for converting the reduction potential of any heme protein into the ratio of the ferric and ferrous heme dissociation constants as well as the difference in free energy of protein folding in the two oxidation states. These results will be discussed in light of current proposals on the necessity of the various porphyrin structures observed in biology.