How can universities engage their critical capabilities in out-of-region efforts that enhance the viability of rural regions in an innovation-based, global economy while simultaneously benefiting the university’s discovery, learning, and outreach missions? This article describes Virginia Tech’s program activities and how they were implemented as the university embraced a broad-scale engagement partnership with Southside [central southern] Virginia, bringing together good science and good politics to partner in transforming this economically distressed region.