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Jouke van Dijk opened the most recent issue of Papers in Regional Science with “Long lasting knowledge in Regional Science,” an editorial highlighting the role that the Association”s journal has played in documenting much of the key regional science research since its inception. Publications obviously provide a long lasting chronicle of research in regional science, but I had rather hoped to find in his editorial an actual identification and enumeration of examples of specific long lasting knowledge gleaned from the regional science record. My hopes stemmed from having spent the past year contemplating appropriate content for this Presidential Address on the occasion of our own 50th Anniversary of the Southern Regional Science Association, which itself seemed to be a appropriate time for reflection and contemplation. The choice had narrowed to three related questions. 1. What do we know? 2. What do we want to know? 3. Do we make a difference? I will offer a set of axioms that I believe underlie a wide range of regional science knowledge, identify a set of unknowns that flow from them, and content that for any of what we know to have an impact, to be meaningfully long lasting, its relevance must be actively extended beyond the boundaries of the regional science community. Only then will our knowledge have made a difference. Citing a prominent example of recent national policy directions, I contend that the opportunity to demonstrate regional science relevance has never been greater, and conclude by calling for us to do so.