Why do investments in certain places yield jobs, growth, and prosperity while similar investments made in seemingly identical places fail to produce the desired results? Starting with the observation that innovation clusters spatially across a broad spectrum of industries, my work seeks to understand the mechanisms and institutions that promote the creation of useful knowledge. In my conceptualization, entrepreneurs, as the agents who recognize opportunity, mobilize resources, and create value, are key to the creation of institutions and the building of capacity that will sustain regional economic development. Entrepreneurs benefit from location. But entrepreneurs are also pivotal as agents of change that can transform local communities. The initial event or entrepreneurial spark that gives rise to prosperous regions is not deterministic nor do they automatically set in motion path dependencies that automatically yield successful places. What matters most is human agency—the building of institutions and the myriad public and private decisions that determine what I call the character of place—a spirit of authenticity, engagement, and common purpose.