The use of diafiltration is now the state-of-the-art in the food and beverage, biotech and pharmaceutical industry. In this paper, the advantages and disadvantages of the most common process modes of diafiltration, batch and continuous, are discussed. Further, the new concept of counter-current diafiltration, which leads to a significant reduction of diafiltration liquid consumption, is introduced. The three concepts are compared in a case study of a plant to concentrate a protein solution. In this study, the process layouts are based on a DSS GR 61 membrane (MWCO of 20,000 Dalton and 100% protein rejection) and a DSS plate-and-frame module. Each continuous diafiltration processes consist of 3 pre-filtration steps followed by 2 to 10 diafiltration steps. The different process layouts are optimized and compared considering technical and economical aspects. It is revealed that all three concepts show similar separation performance. However, taking a 4-stage diafiltration process, the continuous diafiltration requires 40% smaller membrane area compared to counter-current diafiltration, but 140% more diafiltration liquid. Further, comparing batch and counter-current diafiltration, the membrane area for counter-current diafiltration is 115% larger, while the diafiltration liquid requirement of batch process is 74% higher. The trends are also reflected in the higher investment cost and membrane area related operating costs of the counter-current diafiltration process but might be balanced by reduced costs for pre-treatment of the diafiltration liquid and concentration/post-treatment of the permeate. Furthermore, the study demonstrates that addition of fresh diafiltration liquid increases the diafiltration liquid consumption but directly reduces investment and membrane area related operating costs. It can be therefore concluded that counter-current diafiltration is a novel approach to develop case-specific optimized diafiltration processes.