The attack on the World Trade Center (WTC) on September 11th, 2001 exposed thousands of individuals to an unprecedented mix of chemicals, combustion products and micronized building materials. Clinicians at the Mount Sinai Irving Selikoff Center for Occupational and Environmental Medicine, in partnership with affected stakeholder organizations, developed a medical screening program to evaluate the health status of workers and volunteers who spent time at the WTC site and thus sustained exposure in the aftermath of September 11th. Standardized questionnaires were adapted for use in this unique population and all clinicians underwent training to ensure comparability. The WTC Worker and Volunteer Medical Screening Program (MSP) received federal funding in April 2002 and examinations began in July 2002. The MSP and the follow up medical monitoring program has successfully recruited nearly 22,000 responders, and serves as a model for the rapid development of a medical screening program to assess the health of populations exposed to environmental hazards as a result of natural and man-made disasters. The MSP constitutes a successful screening program for WTC responders. We discuss the challenges that confronted the program; the absence of a prior model for the rapid development of a program to evaluate results from mixed chemical exposures; little documentation of the size of the exposed population or of who might have been exposed; and uncertainty about both the nature and potential severity of immediate and long-term health effects.