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In 2008, the World Health Organization (WHO) International Health Regulations (IHR) Coordination Department, in collaboration with Lyonbiopole (Lyon, France), held a consultation, Cities and Public Health Crises (1). Consultants stated that WHO and national guidance does not always adequately address the challenges their cities face, and they could learn much from each other. This article summarizes these challenges, illustrated by the initial appearance of influenza A pandemic (H1N1) 2009 virus during spring 2009 in Mexico City, Mexico, and New York (NYC), New York, USA (metropolitan area populations 20 million and 19 million, respectively). These megacities may not be representative of cities in low-income countries, which face more daunting problems.