Explaining the growth and change of regions and cities is one of the great challenges for social science. Cities or regions have complex economic development processes that are shaped by an almost infinite range of forces. The frames of reference employed to think about such processes are mostly borrowed from the ‘long view backward’, that is, to how the now-developed economies generated their urban systems at the time they developed, but such an approach must ‘average’ over many development experiences and hence may err in its attribution of causes or in the relationship between universally present causes and nationally or regionally specific contexts. Instead a focus on change and causality, studying cities and regions as forward-moving development processes, should determine what is most relevant in defining the ambitions of the field. This chapter, therefore, seeks to establish how future research investigating regional growth and change might best be adapted to meet the challenges outlined above by outlining the existing branches of spatial economics and their contribution to the debates on regional growth. In particular, attention is paid to the perspectives taken by the New Economic Geography and New Neoclassical Urban Economics branches of the discipline. The focus then turns to exploring the difficulties in identifying the direction of causal relations between the locational choices of firms and workers, as well as the limitations of the methods currently employed. The response of Economic Geography to these difficulties is considered, with the chapter concluding by outlining a framework intended to yield greater insights into processes of regional growth and change.