This article provides a systematic review of recent progress in optimization-based process synthesis. First, we discuss multiscale modeling frameworks featuring targeting approaches, phenomena-based modeling, unit operation–based modeling, and hybrid modeling. Next, we present the expanded scope of process synthesis objectives, highlighting the considerations of sustainability and operability to assure cost-competitive production in an increasingly dynamic market with growing environmental awareness. Then, we review advances in optimization algorithms and tools, including emerging machine learning–and quantum computing–assisted approaches. We conclude by summarizing the advances in and perspectives for process synthesis strategies.