The article considers the factors that impede the sustainable development of entrepreneurship. The results of the studies are presented that prove that spatial development based on the growth of agglomerative formations with time can start to hamper the innovative development of entrepreneurship in the regions. The change of the consolidated innovation index is studied depending on the size of the agglomeration zone and the scope of works in terms of the number of city inhabitants. The reasons limiting prospects of the agglomeration growth of large formations, in particular, the mass outflow of the population to large cities and low natural growth of the population, are researched. The compensatory possibilities of migratory flows have been studied and the expediency of ensuring sustainable entrepreneurship based on the new scheme of spatial development of Russia on the basis of agglomeration transformations, and primarily the formation of non-urban agglomerations, has been proved.