As a founder of the Process Systems Engineering (PSE) discipline, Professor Roger W.H. Sargent had set ambitious goals for a systematic new generation of a process design paradigm based on optimization techniques with the consideration of future uncertainties and operational decisions. In this paper, we present a historical perspective on the milestones in model-based design optimization techniques and the developed tools to solve the resulting complex problems. We examine the progress spanning more than five decades, from the early flexibility analysis and optimal process design under uncertainty to more recent developments on the simultaneous consideration of process design, scheduling, and control. This formidable target towards the grand unification poses unique challenges due to multiple time scales and conflicting objectives. Here, we review the recent progress and propose future research directions.