A new donor history questionnaire, introduced by the American Association of Blood Banks in 2004 and approved by Food and Drug Administration in 2006, is now in widespread use in the United States. The development of this questionnaire involved an in-depth look at the entire system of donor screening questions, and is notable for its use of survey design experts as well as blood banking experts, government agencies, and an ethicist who represented the public interest in developing the actual questions. The end result is a questionnaire that uses capture questions in a time bounded format, donor educational materials, and a medication deferral list. Detailed instructions for donor screeners include follow-up questions in easy-to-follow flow-charts. Most importantly, for the first time in the history of developing donor history questions, all materials were tested for donor comprehension using cognitive interview evaluation. This article discusses the development of the questionnaire, explains the methodology, and describes the thinking and rationale for decisions made during redesign of the questionnaire.