Complex global social-ecological challenges of our time such as climate change, biodiversity loss or, more recently, the Covid-19 pandemic can neither be comprehensively understood nor properly addressed by employing a single disciplinary or sectoral perspective. For this reason, more and more large inter- and transdisciplinary (ITD) initiatives are on the rise, intending to open up the silo-like production of knowledge and to advance the integration of different fields of expertise within academia, but also across science, policy and practice. While the need for ITD initiatives in order to both understand and address the complexity of such global socio-ecological challenges has increasingly been acknowledged by research institutions, funders and public authorities, a question remains concerning the extent to which prevailing conditions suffice for conducting ITD research, particularly in terms of whether the envisioned integration of perspectives and actors really happen in practice. This paper embraces a holistic view on ITD integration by presenting both an analytical framework and empirical insights from three ITD initiatives based in Switzerland dealing with sustainable urban water management, (future) extreme events and cross-sectoral climate impacts and climate services in different socio-economic contexts. The framework is based on critical realist reasoning and employs a structure-agency lens by distinguishing conditions of integration at different structural levels, while also acknowledging the power of actors to shape integration and the respective structures. The paper thereby illustrates and helps diagnose the source of challenges experienced in living up to ITD integration endeavors and how these different structural levels are interrelated and impact ITD integration. We conclude by discussing entry points for action aimed at transforming currently unfavorable structures into favorable ones. We thereby intend to provide, in particular, insights for a wide range of actors interested in making sure that ITD initiatives intended to address the global social-ecological challenges of our time can realize their full integration potential in practice.