This paper gives the author's perspective on some of the open questions and opportunities in process synthesis focusing on separation systems as the application. Driven by energy and environmental concerns and challenged by introduction of new raw materials, this author anticipates significant advances in: (1) novel approaches that integrate experimental studies and process synthesis activities, and multi-scale and surrogate models for accurately capturing the behavior of these unconventional mixtures, (2) systematic generation of alternatives for processing these mixtures, and (3) global, robust, and stochastic optimization for identifying the optimum alternative. This paper is an extended version of a conference paper (Clemaschg 2014) presented at the 8th International Conference on Foundations of Computer-Aided Process Design. (C) 2015 Elsevier Ltd. All rights reserved.