In response to a request from the Congress, NIH is developing a 5-year NIH-wide Strategic Plan to advance its mission to support research in pursuit of fundamental knowledge about the nature and behavior of living systems, and the application of that knowledge to extend healthy life and reduce illness and disability. Senior leadership and staff from all 27 Institutes, Centers, and Offices (ICOs) are contributing to the proposed direction and content of the Strategic Plan, with input from the Advisory Committee to the Director, NIH. The framework below identifies crosscutting areas of research exemplifying the breadth of ICOs’ priorities and aims to outline a set of unifying principles to guide NIH in pursuit of its mission. The goal of this larger NIH-wide strategic plan is not to outline the myriad of important research opportunities for specific disease applications (as that is covered in the strategic plans from each of the ICOs, which will be referenced appropriately), but to highlight major trans-NIH themes. The Strategic Plan is due to the Congress in late December 2015.