An optimization study using a comprehensive 3D, multi-phase, non-isothermal model of a PEM (proton exchange membrane) fuel cell that incorporates significant physical processes and key parameters affecting fuel cell performance is presented and discussed in detail. The model accounts for both gas and liquid phase in the same computational domain, and thus allows for the implementation of phase change inside the gas diffusion layers. The model includes the transport of gaseous species, liquid water, protons, energy, and water dissolved in the ion-conducting polymer. Water is assumed to be exchanged among three phases: liquid, vapour, and dissolved, with equilibrium among these phases being assumed. This model also takes into account convection and diffusion of different species in the channels as well as in the porous gas diffusion layer, heat transfer in the solids as well as in the gases, and electrochemical reactions. The results showed that the present multi-phase model is capable of identifying important parameters for the wetting behaviour of the gas diffusion layers and can be used to identify conditions that might lead to the onset of pore plugging, which has a detrimental effect on the fuel cell performance. This model is used to study the effects of several operating, design, and material parameters on fuel cell performance. Detailed analyses of the fuel cell performance under various operating conditions have been conducted and examined.