Air-cathode microfluidic fuel cells are promising micro-scale power sources that unfortunately undergo substantial performance loss at the cathode. This study therefore develops a mathematical model to gain a better understanding of the fundamental processes and polarization characteristics associated with the MFC air cathode operation so as to find strategies to minimize the cathode polarization. The model is solved for the four regions of an MFC cathode compartment (i.e. gas channel, gas diffusion layer, catalyst layer and electrolyte microchannel), and considers microfluidic flow, species transport, charge transport and multi-step oxygen reduction reactions. Relying on the model, transport and chemical patterns inside the MFC cathode compartment are examined. Corresponding electrode polarization behaviors are analyzed over a wide operating potential range including different forms of resistance. Through a series of model-based parametric studies, it is found that the internal transfer resistance slightly decreases with increasing catalyst layer porosity but can be effectively reduced through a proper control of electrolyte hydrodynamic conditions, indicating microfluidic technology is a powerful tool for enhancing electrochemical cells. Copyright (C) 2011, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.