Among strategies that campus leaders and research administrators employ to spur interdisciplinary research in U.S. higher education, one of the costliest--and increasingly popular--is designated interdisciplinary research spaces and buildings. Yet while interdisciplinary research buildings, often focused on the sciences, stand as significant investments and concrete manifestations of institutional interdisciplinary commitment, empirical research thus far has shed little light on who leads them, the challenges these leaders face, and buildings' broader aims and effectiveness. Using interviews with 26 leaders of and documents related to interdisciplinary research buildings at ten U.S. higher education R1 institutions, this qualitative multi-site case study begins to fill this gap. In probing key issues attending interdisciplinary buildings as a growing tool for research administration and development, this study describes various types of interdisciplinary building leaders; details novel challenges, lessons learned and suggested leadership practices; and explores how leaders already do (and future scholarship might) conceptualize and gauge building effectiveness. In doing so, this work provides novel and timely contributions to the current practice of leading interdisciplinary research efforts and grounds future directions for research.