Central Asia's hydrological systems and environment have undergone incomparable changes during recent decades. By using various geospatial and national databases, the socio-economic-environmental vulnerability of the region's major river basins with regard to stress factors related to governance, economy, social issues, environment, hazards, and water scarcity was assessed. A vulnerability profile for each basin was produced and compared with those of the Asia-Pacific's 10 major river basins. Each of the factors appeared quite important for the overall vulnerability. It is thus crucial to focus attention holistically on all the analyzed sectors when trying to solve the challenges in Central Asian waters.