Recent developments in the rational design of purification processes for recombinant proteins are discussed. A review of the main issues involved in process design for protein separation and purification is presented with particular emphasis on the challenges posed by recombinant proteins. This includes physicochemical characterization of target protein and main contaminants, the use of rigorous mathematical modeling and process simulation as well as the development of an expert system and the application of this technology for optimization and design of large scale processes. An expert system for selection of optimal protein separation sequences will give the user a number of alternatives chosen on the basis of extensive data back-up on proteins and unit operations.