Biology is reaching a convergence point of its historic reductionist and modern holistic approaches to understanding the living system. Structural biology has historically taken the reductionist approach to deeply probe the inner workings of complex molecular machines. In contrast, systems biology and genome-scale modeling have organically grown out of the wealth of data now being generated by diverse omics measurements. In the late 2000s, a proposed interdisciplinary field of structural systems biology pitched the merger of these two approaches, with widespread applications in pharmacology, disease modeling, protein engineering, and evolutionary studies. In this commentary, we highlight the challenges of integrating these two fields, with a focus on genome-scale metabolic modeling, and the novel findings that are made possible from such a merger.