Mediated fuel cells are electrochemical devices that produce power in a manner similar to that of conventional proton exchange membrane fuel cells (PEMFCs). They differ from PEMFCs in their use of redox mediators dissolved in liquid electrolyte to conduct oxidation of the fuel or reduction of the oxidant, typically O-2, in bulk solution. The mediators transport electrons (and often protons) between the electrode and the catalysts or chemical reagents in solution. This strategy can help overcome many of the challenges associated with conventional fuel cells, including managing complex multiphase reactions (as in O-2 reduction) or the use of challenging or heterogeneous fuels, such as hydrocarbons, polyols, and biomass. Mediators are also commonly used in enzymatic fuel cells, where direct electron transfer from the electrode to the enzymatic active site can be slow. This review provides a comprehensive survey of historical and recent mediated fuel cell efforts, including applications using chemical and enzymatic catalysts.