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The structure of a settlement network has been influenced historically by physical, geographical and socioeconomic factors. Theories of spatial development have focused on the interaction between urban areas and socioeconomic processes considering the natural surroundings as a steady parameter rather than a potentially varying element contributing to spatial development. Over the past 25 years in Greece, a number of socio-economic factors along with improvements in transport infrastructure led to crucial changes in the traditional settlement system. The development of new economic activities was often associated with the special characteristics of the natural landscape. In this way, natural landscape as a dynamic element interacts with the built environment and the economic activities of a place, leading to the formation of new clusters of relationships. Using the case study of the Region of Western Macedonia, a mountainous, border zone Greek region, and based on an interactive framework of analysis whereby human and natural systems are considered strongly interconnected, this paper examines the spatial interactions between the settlement network, as the basic representation of human activity, the natural landscape, as a crucial element of the natural system, and the dynamic zones of economic activities, as a parameter that encompasses crucial attributes of both human and natural systems. The paper proposes that the heterogeneity of these interactions and the way they affect the thresholds and resilience of a specific place are important for the understanding of spatial change and for an integrated spatial planning for sustainable …