Unconventional oil and natural gas development is a driving force behind significant economic and energy policy shifts in the United States and the world today. Technological advances in development are substantially increasing energy supplies, while at the same time outpacing the scientific research that can answer questions about the development’s potential effects. With funding from private foundations, HEI convened a Special Scientific Committee to develop an impartial, multidisciplinary Strategic Research Agenda to help guide future research about potential adverse impacts of 21st century oil and natural gas development. The Research Agenda was developed in response to questions raised in the Appalachian region of the United States. The questions are not unique to the region; therefore, the Research Agenda can address concerns expressed elsewhere in the United States and the world.