The three general approaches to empirical work in economics are structural, experimentalist, and descriptive. This paper provides an overview of how empirical work in regional economics fits into these three categories. In particular, I examine a single issue in the field, the nature of agglomeration benefits and the productivity gains from agglomeration, and analyze the advantages and drawbacks of following each of these three empirical approaches. I also discuss potentially fruitful ways empirical work in regional economics might advance. Copyright (c) 2010, Wiley Periodicals, Inc.