Salinity Gradient Power by Reverse Electrodialysis (SGP-RE) technology allows the production of electricity from the different chemical potentials of two differently concentrated salty solutions flowing in alternate channels suitably separated by selective ion exchange membranes. In SGP-RE, as well as in conventional ElectroDialysis (ED) technology, the process performance dramatically depends on the stack geometry and the internal fluid dynamics conditions: optimizing the system geometry in order to guarantee lower pressure drops (ΔP) and uniform flow rates distribution within the channels is a topic of primary importance. Although literature studies on Computational Fluid Dynamics (CFD) analysis and optimization of spacer-filled channels have been recently increasing in number and range of applications, only a few efforts have been focused on the analysis of the overall performance of the process. In particular, the proper attention should be devoted to verify whether the spacer geometry optimization really represents the main factor affecting the overall process performance. In the present work, realized within the EU-FP7 funded REAPower project, CFD simulations were carried out in order to assess the effects of different parameters on the global process efficiency, such as the choice of spacer material and morphology, and the optimization of feed and blowdown distribution systems. Spacer material and morphology can affect the fluid dynamics inside each channel. In particular, the appropriate choice of net spacer material can influence the slip/no-slip condition of the flow on the spacer wires, thus significantly affecting the channel fluid dynamics in terms of pressure drops. A Unit Cell approach was adopted to investigate the effect of the different choices on the fluid flow along the channel. Also, the possibility of choosing a porous medium to substitute the net spacer was theoretically addressed. Such investigation focused on the porosity and the fiber radius required to respect the process constrains of pressure drops and mechanical stability. On the other hand, the overall pressure drops of a SGP-RE or ED stack can be considered as resulting from different contributions: the pressure drop relevant to the feed distributor, the pressure drop inside the channel, and the pressure drop in the discharging collector. The choice of the optimal stack geometry is, therefore, strongly related to the need of both minimizing each of the above terms and obtaining the most uniform feed streams distribution among the stack channels. In order to investigate such aspects, simulations were performed on a simplified ideal planar stack with either 50 spacer-less or 50 spacer-filled channels. The effect of the distribution/collector channel thickness and geometry on single-channel flow rates and overall pressure drops in the system was analyzed and a significant influence of distributor layout and size on the overall process performance was found.