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Urgent sustainability challenges require efective leadership for inter- and trans-disciplinary (ITD) institutions. Based on the diverse experiences of 20 ITD institutional leaders and specifc case studies, this article distills key lessons learned from multiple pathways to building successful programs. The lessons refect both the successes and failures our group has experienced, to suggest how to cultivate appropriate and efective leadership, and generate the resources necessary for leading ITD programs. We present two contrasting pathways toward ITD organizations: one is to establish a new organization and the other is to merge existing organizations. We illustrate how both beneft from a real-world focus, with multiple examples of trajectories of ITD organizations. Our diverse international experiences demonstrate ways to cultivate appropriate leadership qualities and skills, especially the ability to create and foster vision beyond the status quo; collaborative leadership and partnerships; shared culture; communications to multiple audiences; appropriate monitoring and evaluation; and perseverance. We identifed fve kinds of resources for success: (1) intellectual resources; (2) institutional policies; (3) fnancial resources; (4) physical infrastructure; and (5) governing boards. We provide illustrations based on our extensive experience in supporting success and learning from failure, and provide a framework that articulates the major facets of leadership in inter- and trans-disciplinary organizations: learning, supporting, sharing, and training.