In terms of subnational entities such as urban agglomerations, provinces, and counties, regions are major arenas in which knowledge-producing and knowledge-exploiting activities are rooted, with marketable innovative products or processes emerging from the location-specific interplay of economic, social, cultural, technological, and political factors (Malecki, 1997, 2000; Meusburger, 2000, 2008). Presumably, there is something fundamentally 'spatial" and "place-bound" that determines the abilities of corporate actors to innovate. There are also certain constellations of factors that shape spaces of innovation, understood as outstanding agglomerations of firms and other organizations that successfully engage in the generation and economic exploitation of knowledge-intensive activities. Because creativity is important in inducing innovativeness, the notions of spaces of innovation and milieus of creativity are, logically, strongly linked, as I show in this chapter.Like regional economists, economic geographers have been exploring relevant dynamics and determinants of the knowledge-based economy for several decades, filling entire libraries with their writings (for recent synopses, see Cooke et al., 2007; Simmie, 2005). In the following pages I draw on a range of these works to present currently prominent chains of argumentation and perspectives. I discuss key terminological, conceptual, and empirical foundations, trying to open the black box of why and how innovative spaces and regional knowledge economies evolve in response to the dynamics of an environment that enhances creativity.