This “white paper” is a concise perspective based on a session during FIPSE 3, held in Rhodes, Greece, June 20–23, 2016. This was the third conference in the series “Future Innovation in Process Systems Engineering” (http://fi-in-pse.org), which takes place every other year in Greece, with a limited number of participants and just three topics/sessions whose objective is to pose and discuss open research challenges in Process Systems Engineering. This specific session comprised invited talks by Sigurd Skogestad and Iiro Harjunkoski, followed by short presentations by the participants and extensive discussions. The paper does not intend to provide a comprehensive review on the subject, or a detailed exposition of the concepts and problems. Its aim is to highlight open problems and directions for future research.