The percentage of the world's population living in urban areas will increase from 50% in 2008 to 70% (4.9 billion) in 2025. Crowded urban areas in developing and industrialized countries are uniquely vulnerable to public health crises and face daunting challenges in surveillance, response, and public communication. The revised International Health Regulations require all countries to have core surveillance and response capacity by 2012. Innovative approaches are needed because traditional local-level strategies may not be easily scalable upward to meet the needs of huge, densely populated cities, especially in developing countries. The responses of Mexico City and New York City to the initial appearance of influenza A pandemic (H1N1) 2009 virus during spring 2009 illustrate some of the new challenges and creative response strategies that will increasingly be needed in cities worldwide.