The relationship between inter- and transdisciplinary research and potentially transformative science is poorly understood. We use a case study of a long-term transdisciplinary research effort on hantaviruses combined with findings from studies of team science to generate a hypothesized model that links cross-disciplinary collaboration with transformative scientific outcomes. We show that potentially transformative research depends on the existence of an interesting and worthwhile problem to which participants can contribute in salient ways, human and material foundations within disciplines, collaborative mutualism across disciplines, and a transformative learning process that enables knowledge integration across diverse perspectives. Transformative learning theory suggests that new, integrated conceptual understanding is initiated by disorienting dilemmas. We argue that engagement in cross-disciplinary collaboration produces disorienting dilemmas that initiate transformative learning. Our hypothesized model provides a generalized framework for understanding how transformative learning occurs in cross-disciplinary collaboration and how that can lead to transformative science.