This chapter provides a detailed discussion of the research approach and methods employed in the Canadian Regional Development project. The research methods section identifies and discusses the approach taken by the research team, including an overview of the mixed method case study approach employed, the structure of the research team, an overview of the case study regions, and the details of data collection, analysis, and knowledge mobilization efforts. This is followed by a critical reflection on the methods and lessons learned from the experiences of the research team, including a discussion of the strengths and challenges associated with large, interdisciplinary, cross-country case study projects, and how the research team approached the challenges encountered. While there has been growing recognition of the importance of interdisciplinary research, progress in actualizing this type of research has been slow. This chapter provides insights into such an actualization, detailing the planning and execution of a multi-level, team-based, interdisciplinary research study across a large geography over a multi-year time frame. It is our hope that the lessons from the Canadian Regional Development project will have transferable value for others engaged in similar research endeavours.