Nafion is the first and the most well-known and commonly used ionomer membrane, applied nowadays in a broad variety of applications. This wide suitableness comes up in last instance from its chemical structure: a hydrophobic polytetrafluoroethylene backbone containing regularly spaced long perfluorovinyl ether pendant side chains ended by a sulfonic group. It is widely accepted that Nafion self-organizes in a membrane to form hydrophilic and hydrophobic domains in a way that is not yet perfectly understood. Despite there have been several models under debate, the pioneering cluster-network model (in which the polymer chains form reverse micelles with sulfonic groups lined in the wall and encapsulating water cavities) proposed by Gierke et al. is frequently reported in the literature. With the rise of Nanotechnology, a brilliant idea carne up less than two decades ago: the use of hydrated clusters as reactive vessels for the synthesis of a myriad of nanoparticles (NPs). Nevertheless, most of the works ascribed the formation of NPs to the cluster network model although most of the obtained NPs usually displayed diameters above the theoretical size of clusters and channels and that the local distribution of NPs seemed not to follow the original model. Lately, some authors, while studying the formation of NPs inside Nafion matrix, claim that all these disparities suggest that the role played by the flexible morphology of the polymer as well as the role of the solvent swelling the polymer have been oversimplified. Accordingly, this chapter will review the state-of-the-art of the several models describing Nafion's morphology and will provide a wide overview of their implication in the synthesis of NPs