This article, based on the inaugural Andrew Isserman lecture, explores whether regional science has lived up to its founder’s aspirations to create an interdisciplinary and international field to tackle key societal problems with reasoning, evidence, and sound policy recommendations. I distinguish methods-driven research from problem-driven research and illustrate the pitfalls of the former with the emergence and use of economic base multipliers from export base theory. Then, beginning with Walter Isard’s bold vision in the first issue of the International Regional Science Review, I follow the evolution of the Review under Andrew Isserman’s three decades of editorship, exploring the difference between methods-driven and descriptive research articles and those addressed to regional problem solving. Editor Isserman actively sought out scholars and special issue editors with an interest in policy and a willingness to work across disciplines and borders. He raised funding for themed conferences that would yield exciting new articles, a practice his coeditors and successors have continued. In his own research, despite his love of methods and facility with them, Isserman often chose to work on important regional problems such as whether the Appalachian program had produced real personal income gains, how the Soviet Union should pursue regional development under perestroika, and in recent years, rural poverty and agriculture and biotechnology. From work on deindustrialization and military industrial conversion, I argue that exposure to the intricacies of real-world policy making strengthens both theory and empirical research.