The cake layer deposited on the membrane modules of membrane bioreactors (MBRs), especially under a submerged configuration, represents a relevant and fundamental mechanism deeply influencing the development of membrane fouling. It negatively affects the total resistance to filtration, while exerting a positive effect as a “pre-filter” promoting the “dynamic membrane” that protects the physical membrane from internal fouling. These two opposite phenomena should be properly managed, where the submerged membranes are usually subjected to a periodical cake layer removal through ordinary (permeate backwashing and air scouring) and/or irregular cleaning actions (manual physical cleaning). In this context, the physical removal of the cake layer is needed to maintain the design filtration characteristics. Nevertheless, the proper evaluation of the effect of physical cleaning operations is still contradictory and under discussion, referring in particular to the correct evaluation of fouling mechanisms. The aim of the present work was to summarize the different aspects that influence the fouling investigations, based on simple models for the evaluation of the resistance to filtration due to the cake layer, through physical cleaning operations.