The key to successful and efficient protein purification is the selection of the most appropriate purification techniques and their combination in a logical way to obtain the desired purification in the minimum number of steps. However, the rationalization of protein purification process development is faced with a number of challenges. In this paper, the challenges in protein purification process development are captured. The state-of-the-art in protein purification process synthesis and design is reviewed and the strengths and weaknesses of the current strategies highlighted. Finally, views on the future directions of protein purification process development are presented. (c) 2007 Society of Chemical Industry.