The aim of this work is to understand the molecular evolution of iron-sulfur clusters in terms of electronic structure and function. Metal-substituted models of biological [Fe4S4] clusters in oxidation states [MxFC4-xS4](3+5/2+/1+) have been studied by density functional theory (M = Cr, Mn, Fe, Co, Ni, Cu, Zn, and Pd, with x = I or 2). Most of these clusters have not been characterized before. For those that have been characterized experimentally, very good agreement is obtained, implying that also the predicted structures and properties of new clusters are accurate. Mean absolute errors are 0.024 angstrom for bond lengths ([Fe4S4], [NiFe3S4], [CoFe3S4]) and 0.09 V for shifts in reduction potentials relative to the [Fe4S4] cluster. All structures form cuboidal geometries similar to the all-iron clusters, except the Pd-substituted clusters, which instead form highly distorted trigonal and tetragonal local sites in compromised, pseudocuboidal geometries. In contrast to other electron-transfer sites, cytochromes, blue copper proteins, and smaller iron-sulfur clusters, we find that the [Fe4S4] clusters are very insensitive to metal substitution, displaying quite small changes in reorganization energies and reduction potentials upon substitution. Thus, the [Fe4S4] clusters have an evolutionary advantage in being robust to pollution from other metals, still retaining function. We analyze in detail the electronic structure of individual clusters and rationalize spin couplings and redox activity. Often, several configurations are very close in energy, implying possible use as spin-crossover systems, and spin states are predicted accurately in all but one case ([CuFe3S4]). The results are anticipated to be helpful in defining new molecular systems with catalytic and magnetic properties.