In the context of growing urbanization and climate change, the issue of how to best secure and increase future water supply in developing countries is key. To support informed decision-making in Mexico City, a comprehensive study was conducted to assess the potential effects of climate change and the vulnerability of water sources. The infrastructural, environmental and administrative factors affecting the water available from each source were identified and evaluated, and then combined with the likely impacts in regional water availability estimated using results from two global circulation models and two emission scenarios. The results obtained indicate that the water sources outside Mexico City, such as the Cutzamala and Lerma systems, are the most vulnerable. The current situation is likely to become worse as a result of climate change, as projections suggest a 10–17% reduction in water availability by 2050. When responsible agencies decide the strategies to secure and increase water supply, they will have to consider the prevailing and potential conflicts, the local water demand, the contribution to the city's greenhouse gas emissions and future changes in water availability.