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The problem of asymmetry, uneven development has been the most important problem of the state for a long time. The concept of asymmetry is multifaceted, and can manifest itself in various aspects of the development of the region. The article identifies the prerequisites for differentiation, asymmetry, which are diverse and related both to natural and climatic, as well as to historical, political, and economic conditions. Each constituent entity of the federation, developing its own strategy of innovative development, should take into account both state priorities and the opportunities and specifics of regional development and their competitive advantages in specific science-intensive industries. Among the main prerequisites objectively contributing to the disproportion of the socioeconomic status of the subjects of the South of Russia are the following: area size, demography (number and density of population), geolocation, etc. As a result of the study of the differentiation of the socio-economic development of the regions of the Southern Federal District, the authors note a certain tendency: for several years inequality in the explored development of regions exists, but it is not dynamic. The graduation of the regions, with respect to practically every indicators considered, remains unchanged. The dynamics is observed only relative to the base value of the indicator for each of the subjects of the district, without violating the overall degree of differentiation. Consequently, the existence of strategies for socio-economic development of the regions is not yet a guarantee that development in these regions will reach a new trajectory. Many external and internal factors can influence it. Nevertheless, it is necessary to know the guidelines of innovative development and to look for ways out of the existing imbalance in this development. Thus, developing their own strategy of innovative development, regions need to create starting conditions for further development, increasing production and socio-economic sphere.