Electrogenic bacteria have evolved with a tendency to oxidize various organic matter and donate electrons to terminal electron acceptors. This forms the basis for power generation by microbe-driven fuel cells when these electro-active bacteria interact with electrodes. Depending on an electrode's potential for oxidation of an electron donor at an anode (E ano) compared to the reduction of an electron acceptor at a cathode (E cat), a net positive/negative potential difference (ΔE) will arise. Correspondingly, a positive ΔE will result in power generation (microbial fuel cells, MFCs) while negative ΔE requires power (microbial electrolysis cells). Herein, various factors that reduce power efficiency in MFCs, compared to theoretical calculations and their troubleshooting, are discussed. Furthermore, eco-physiological studies of electrogenic bacteria, in relation to their electron transfer molecular mechanisms when grown in varying electron donor-acceptor ratios are also discussed. Hence, the information with respect to the choice of an electrogen, the type of inocula, and electrode material (depending on the terminal electron acceptor) for the development of novel MFCs is understood. Finally, improvements of anode performance in MFCs, using advances in nanotechnology were explored to generate ideas for enhancing power densities. Altogether, a combinatorial approach in the discovery of electrogenic molecular mechanisms, along with improving the existing electrode material, can significantly enhance the generation of alternative and eco-friendly electricity.