In recent years, Russia has faced serious global challenges. Particular attention is required for demographic challenges, which are caused by natural population decline, ambiguous migration processes, and their exacerbation due to the spread of the coronavirus infection and subsequently the aggravation of the foreign policy situation. The largest Russian cities are centers of economic growth with significant potential for solving regional livelihood problems. An important indicator of the state and development of a city as a socio-economic system is the change in population size. The dynamics of demographic and other socio-economic indicators deserve detailed analysis and study. The results obtained must be considered when making strategic decisions and developing adaptation mechanisms. In the past five years, a natural population decline has prevailed in the studied largest municipalities, which is only partially offset by migration growth. In most cities with a population of over one million, there is a correlation between the dynamics of population growth (both natural and migration), the average wage level, and the quality of the urban environment. In cities with migration outflow, measures are needed to improve these parameters. Since all cities have developed industries, including due to natural and historical factors, systematic monitoring of the relevant indicators and a detailed analysis of the reasons for negative trends, including demographic ones, are important for ensuring balanced economic development. To ensure the balance of supply and demand in the labor market in terms of qualification and professional requirements and expectations, the implementation of regional programs and projects with the participation of government and business is proposed. In the context of the economic development of the largest cities and adaptation to global challenges, it is proposed that government authorities, local governments, the scientific community, and businesses identify new promising specializations for cities, including the need to enhance import substitution and implement high-tech, science-intensive industries.