Membrane fouling remains a major problem in applications of microfiltration for particle removal, sterile filtration, and clarification. The theoretical framework presented in this chapter provides a completely new approach for the analysis and interpretation of flux decline data obtained in these membrane systems. The model explicitly accounts for fouling due to surface (pore) blockage and cake filtration, with the cake forming over those regions of the membrane that have first been covered by large aggregates. Just as importantly, this new theoretical framework provides the first quantitative analysis of the effects of the pore morphology on the rate of flux decline. Membranes with straight-through pores show the greatest rate of flux decline since the particles completely cover (block) the non-interconnected pores in these membranes. In contrast, particle deposition on the surface of a homogeneous membrane with highly interconnected pores will disturb the filtrate flow only over a relatively small penetration distance into the membrane pore structure. This implies that very thick membranes should exhibit a slower rate of flux decline due to the smaller relative disturbance in the flow, an effect that has been confirmed experimentally [16,17]. The flux decline for composite membrane structures shows a more complex behavior. The surface fouling completely blocks the pores in the upper skin layer, but the fluid rapidly redistributes itself through the very highly interconnected pores within the membrane substructure. This causes a shunting of the fluid flow towards the remaining open pores, leading to a reduction in the rate of flux decline compared to that for a single membrane layer. This theoretical analysis also provides a framework that can be used for the design and development of new membrane structures having reduced rates of fouling. This would include the proper choice of pore connectivity, membrane thickness, and the specific properties of the individual layers in more complex composite structures. These phenomena have often been neglected in membrane design/development, although they can clearly have a dramatic effect on the flow distribution, fouling, and overall selectivity for the particular separation.