The objective of this study was to identify key issues relevant to the development and implementation of a macro-level priority-setting framework (i.e., across broad service areas) within the Calgary Health Region. We used rigorous qualitative methods, including focus groups, meeting observations and interviews to identify views of decision-makers. Key issues relevant to macro-level priority-setting included: application of evidence, incentives, physician involvement, public involvement and application of values. Detailed insight into each of these issues was derived, including how best to handle related barriers to priority-setting in health organizations and important lessons for framework development. These lessons learned should provide insight for similar activity in other jurisdictions.