The damage to human life, property, and infrastructure by natural disasters has been growing exponentially for the past 40 years. The driving force of this development is the increase in exposure and vulnerability of human society to the impacts of disasters. On the other hand, significant local, regional and global capacities for disaster reduction have been built since the beginning of the UN International Decade for Natural Disaster Reduction in 1990. It remains unclear how the race between mitigation efforts and expanding disaster potential will develop in the coming years. This is a report on the risk potential of megacities and the strategies to reduce such risk, drawing on the experience of 8 years work in the Earthquakes and Megacities Initiative (www.earthquakesandmegacities.org/). The crucial role of science in this process will be discussed.