One of the major needs for medical schools and health systems in less affluent countries is system strengthening through the training and development of faculty, doctors, nurses, and other skilled health care workers. Partnering with medical schools in more affluent countries such as the United States is one potential approach for medical schools in underresourced areas, such as Sub-Saharan Africa. Most commonly, these partnerships have focused on research agendas or limited educational exchanges. In this perspective, the authors present an approach to strengthening collaborative relationships between three medical schools in the United States and four in Sub-Saharan Africa. The approach is explicitly focused on achieving partnerships that enable institutions to improve care. It developed from an initiative to fund partnerships or "collaboratives" that address 10 key learning questions determined to be central to focusing efforts on strengthening education systems and, in turn, improving health in Sub-Saharan Africa. The leaders of the schools involved in these partnerships met multiple times across three years to discuss how their collaboratives could address the ten learning questions including what is the best approach and what are the key ingredients for creating effective, multidimensional collaborations between academic institutions in the North and institutions in Sub-Saharan Africa. Collaboratively, they defined a framework of evidence that can be used for evaluating their current initiatives and, potentially, for structuring future partnerships.