Synthesizing heterogeneous findings from different scientific disciplines, thematic fields, and professional sectors is considered to be a critical component of inter- and transdisciplinary research endeavors. However, little is known about the complex interplay between synthesizing heterogeneous findings, leading creative synthesis, and learning about leading and synthesizing. In the present article, we therefore focus on the key interactions between leading and synthesizing, between synthesizing and learning, and between learning and leading in inter- and transdisciplinary contexts and compile a set of 21 principles that guide the interactions between these components. We use these principles to reflect ex post on the benefits and challenges we encountered in developing a nationwide monitoring program for river restoration in Switzerland and draw lessons learned for future inter- and transdisciplinary research endeavors. We conclude that learning and synthesizing do not happen on their own but need to be designed as intentional and purposeful processes.