Clinical teams are of growing importance to healthcare delivery, but little is known about how teams learn and change their clinical practice. We examined how teams in three US hospitals succeeded in making significant practice improvements in the area of antimicrobial resistance. This was a qualitative cross-case study employing Soft Knowledge Systems as a conceptual framework. The purpose was to describe how teams produced, obtained, and used knowledge and information to bring about successful change. A purposeful sampling strategy was used to maximize variation between cases. Data were collected through interviews, archival document review, and direct observation. Individual case data were analyzed through a two-phase coding process followed by the cross-case analysis. Project teams varied in size and were multidisciplinary. Each project had more than one champion, only some of whom were physicians. Team members obtained relevant knowledge and information from multiple sources including the scientific literature, experts, external organizations, and their own experience. The success of these projects hinged on the teams' ability to blend scientific evidence, practical knowledge, and clinical data. Practice change was a longitudinal, iterative learning process during which teams continued to acquire, produce, and synthesize relevant knowledge and information and test different strategies until they found a workable solution to their problem. This study adds to our understanding of how teams learn and change, showing that innovation can take the form of an iterative, ongoing process in which bits of K&I are assembled from multiple sources into potential solutions that are then tested. It suggests that existing approaches to assessing the impact of continuing education activities may overlook significant contributions and more attention should be given to the role that practical knowledge plays in the change process in addition to scientific knowledge.