System-of-systems approaches for integrated assessments have become prevalent in recent years. Such approaches integrate a variety of models from different disciplines and modeling paradigms to represent a socio-environmental (or social-ecological) system aiming to holistically inform policy and decision-making processes. Central to the system-of-systems approaches is the representation of systems in a multi-tier framework with nested scales. Current modeling paradigms, however, have disciplinary-specific lineage, leading to inconsistencies in the conceptualization and integration of socio-environmental systems. In this paper, a multidisciplinary team of researchers, from engineering, natural and social sciences, have come together to detail socio-technical practices and challenges that arise in the consideration of scale throughout the socio-environmental modeling process. We identify key paths forward, focused on explicit consideration of scale and uncertainty, strengthening interdisciplinary communication, and improvement of the documentation process. We call for a grand vision (and commensurate funding) for holistic system-of-systems research that engages researchers, stakeholders, and policy makers in a multi-tiered process for the co-creation of knowledge and solutions to major socio-environmental problems.