Rural depopulation has been a subject of public interest for decades. From the perspective of balanced demographic and social development of Serbia, however, the key role actually belongs to medium-sized towns with up to 100,000 inhabitants. These towns connect villages and small towns to fast-growing large cities. Many of them are shrinking in size and, judging by the experiences of countries in the region, will continue to shrink in the future. Is it possible to stop the decline of these cities and can they adapt to new demographic trends? What strategies are available to border, tourist, industrial and other cities in Serbia and the region? The chapter on urban and spatial aspects of depopulation shows that decentralisation and de-concentration, as well as the development of infrastructure and higher urban functions, are key not only for the balanced development of Serbia but also for its demographic development. A detailed analysis of medium-sized Serbian cities shows that it is possible to develop specific strategies tailored to individual cities and regions that can lead to positive demographic outcomes.