Nearly half a century has passed since the publication of the seminal work of Professor Isard, Location and Space-Economy, which became the basis of a new field called regional science. As indicated by its subtitle (i.e., A General Theory Relating to Industrial Location, Market Areas, Land Use, Trade, and Urban Structure), the book was written with the aim of nothing less than initiating the development of a general theory of location and space-economy, embracing the total spatial array of economic activities. Such a theory was supposed to include both the traditional general equilibrium theory and the international trade theory as special cases. In this paper, first I shall discuss what were his possible ideas on the general theory, given the state of economic science at that time, and what were the main contributions of Location and Space-Economy in initiating the development of such a theory. Second, I review the major contributions of subsequent works by Professor Isard and other scholars from the viewpoint of the development of the general theory. Finally, I discuss possible future directions in developing such a theory.